Nerve stimulator system

ABSTRACT

Devices, systems and methods for treating at least one of a condition or a symptom of a patient by positioning a stimulation device at a target site adjacent to or near a nerve within a patient. The stimulation device comprising an antenna and one or more electrodes. Transmitting electrical energy to the antenna and generating electrical impulses within the stimulation device with the electrical energy and applying the series of electrical impulses to the nerve via the electrode. The electrical impulses sufficient to modulate the nerve and treat the condition or symptom of the patient; and which have on periods where the electrical impulses are generated and applied to the nerve and off periods between the electrical impulses, where the electrical energy is transmitted to the antenna.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Nonprovisionalapplication Ser. No. 14/071,577 filed 4. Nov. 2013, now U.S. Patent No.9,205,258 issued 8 Dec. 2015; which is incorporated herein by referencein its entirety.

FIELD

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theenergy impulses (and/or fields) that are used to treat those conditionscomprise electrical and/or electromagnetic energy, which are deliveredto nerve or other tissue of a patient.

BACKGROUND OF THE INVENTION

The use of electrical stimulation for treatment of medical conditions iswell known. One of the most successful applications of modernunderstanding of the electrophysiological relationship between muscleand nerves is the cardiac pacemaker. Although origins of the cardiacpacemaker extend back into the 1800's, it was not until 1950 that thefirst practical, albeit external and bulky, pacemaker was developed. Thefirst truly functional, wearable pacemaker appeared in 1957, and in1960, the first fully implantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667, entitled Implantable medical device for treating cardiacmechanical dysfunction by electrical stimulation, to DENO et al).Because the leads are implanted within the patient, the pacemaker is anexample of an implantable medical device.

Another such example is electrical stimulation of the brain withimplanted electrodes (deep brain stimulation), which has been approvedfor use in the treatment of various conditions, including pain andmovement disorders such as essential tremor and Parkinson's disease[Joel S. PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu.Rev. Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92(2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST et al].

Many other forms of nerve stimulation exist [HATZIS A, Stranjalis G,Megapanos C, Sdrolias P G, Panourias I G, Sakas D E. The current rangeof neuromodulatory devices and related technologies. Acta NeurochirSuppl 97(Pt 1, 2007):21-29]. The type of electrical stimulation that ismost relevant to the present invention is vagus nerve stimulation (VNS,also known as vagal nerve stimulation). It was developed initially forthe treatment of partial onset epilepsy and was subsequently developedfor the treatment of depression and other disorders. The left vagusnerve is ordinarily stimulated at a location within the neck by firstimplanting an electrode about the vagus nerve during open neck surgeryand by then connecting the electrode to an electrical stimulator circuit(a pulse generator). The pulse generator is ordinarily implantedsubcutaneously within a subcutaneous pocket that is created at somedistance from the electrode, which is usually in the leftinfraclavicular region of the chest, but it may also be implanted in adeeper pocket beneath the pectoralis major muscle. A lead is thentunneled subcutaneously to connect the electrode assembly and pulsegenerator. The patient's stimulation protocol is then programmed using adevice (a programmer) that communicates with the pulse generator, withthe objective of selecting stimulation parameters that best treat thepatient's condition (pulse frequency, stimulation amplitude, pulsewidth, etc.)[U.S. Pat. No. 4,702,254 entitled Neurocyberneticprosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nervestimulation techniques for treatment of epileptic seizures, to OSORIO etal; U.S. Pat. No. 5,299,569 entitled Treatment of neuropsychiatricdisorders by nerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M.Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation, vagal nervestimulation and transcranial stimulation: An overview of stimulationparameters and neurotransmitter release. Neuroscience and BiobehavioralReviews 33 (2009):1042-1060; GROVES D A, Brown V J. Vagal nervestimulation: a review of its applications and potential mechanisms thatmediate its clinical effects. Neurosci Biobehav Rev 29(2005):493-500;Reese TERRY, Jr. Vagus nerve stimulation: a proven therapy for treatmentof epilepsy strives to improve efficacy and expand applications. ConfProc IEEE Eng Med Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE.Vagus nerve stimulation: current concepts. Neurosurg Focus 25 (3,2008):E9, pp. 1-4; ANDREWS, R. J. Neuromodulation. I. Techniques-deepbrain stimulation, vagus nerve stimulation, and transcranial magneticstimulation. Ann. N. Y. Acad. Sci. 993(2003):1-13; LABINER, D. M.,Ahern, G. L. Vagus nerve stimulation therapy in depression and epilepsy:therapeutic parameter settings. Acta. Neurol. Scand. 115(2007):23-33;AMAR, A. P., Levy, M. L., Liu, C. Y., Apuzzo, M. L. J. Vagus nervestimulation. Proceedings of the IEEE 96(7, 2008):1142-1151; BEEKWILDER JP, Beems T. Overview of the clinical applications of vagus nervestimulation. J Clin Neurophysiol 27(2, 2010):130-138; CLANCY J A,Deuchars S A, Deuchars J. The wonders of the Wanderer. Exp Physiol 98(1,2013):38-45].

For vagus nerve stimulators that are currently implanted in patients,the pulse generator contains a battery that powers the system. Withtypical stimulator settings, the battery life range may be as long as6.6 to 10 years, but maybe as short as less than two years. Eventuallythe battery must be surgically replaced when it is at or near the limitof its lifetime [Depression Patient's Manual for Vagus Nerve Stimulationwith the VNS Therapy System. Document REF 26-0005-6000/1, 2004.Cyberonics Inc. 100 Cyberonics Boulevard, Houston, Tex. U.S.A. 77058;VONCK K, Dedeurwaerdere S, De Groote L, Thadani V, Claeys P, Gossiaux F,Van Roost D, Boon P. Generator replacement in epilepsy patients treatedwith vagus nerve stimulation. Seizure 14(2, 2005):89-99].

However, beginning with some of the earliest implantable systems, nervestimulators have been developed that contain no battery whatsoever, orthat use a rechargeable battery that is charged by an energy sourcesituated outside the body of the patient. Already in 1934, CHAFFEE andLIGHT successfully stimulated the thoracic vagus nerve of an animal withan implanted electrode powered only by an externally appliedelectromagnetic field, as evidenced by the production of gastric acidfrom the animal [E. Leon CHAFFEE and Richard U. Light. A Method for theRemote Control of Electrical Stimulation of the Nervous System. Yale JBiol Med7(2, 1934): 83-128]. Smaller implanted peripheral nerve andbrain stimulators that had no battery were subsequently developed foruse in patients in the 1960s [William W. L. GLENN, John H. Hageman,Alexander Mauro, Lawrence Eisenberg, Stevenson Flanigan, and MarvinHarvard. Electrical Stimulation of Excitable Tissue by Radio-FrequencyTransmission. Ann Surg 160(3, 1964):338-350; DELGADO J M.Radiostimulation of the brain in primates and man. Anesth Analg 48(4,1969):529-542]. Such systems transfer energy inductively to theimplanted stimulator, from a coil outside the patient's body to animplanted coil, such that the implanted coil supplies power to thestimulator's electrodes or to an implanted rechargeable battery [U.S.Pat. No. 3,727,616, entitled Electronic system for the stimulation ofbiological systems, to LENKES; U.S. Pat. No. 7,813,809, entitledImplantable pulse generator for providing functional and/or therapeuticstimulation of muscles and/or nerves and/or central nervous systemtissue, to STROTHER et al; U.S. Pat. No. 8,369,959, entitled Implantablemedical device with integrated antenna system, to MESKENS; U.S. Pat. No.6,782,292, entitled System and method for treatment of mood and/oranxiety disorders by electrical brain stimulation and/or drug infusion,to WHITEHURST; application US20030212440, entitled Method and system formodulating the vagus nerve (10th cranial nerve) using modulatedelectrical pulses with an inductively coupled stimulation system, toBOVEJA].

Such inductive systems may also be used for bidirectional telemetry ofdevice parameter settings and physiological data, irrespective ofwhether the devices are also powered by induction coils [Robert PUERSand Jef Thoné. Short distance wireless communications. Chapter 7, pp.219-277, In: H.-J. Yoo, C. van Hoof (eds.), Bio-Medical CMOS ICs. NewYork:Springer, 2011; U.S. Pat. No. 5,186,170, entitled Simultaneousradio frequency and magnetic field microprocessor reset circuit, toVARRICHIO et al]. Intrinsic limitations of such coil-based poweringsystems are that the source oscillating magnetic field must be in closeproximity to the implanted pickup coil in order to transfer the energyefficiently (e.g., applied to the patient's skin), and the source andpickup coils have to be optimally oriented with respect to one another.The frequencies of oscillations for those systems involving magneticinduction are typically less than 100 MHz.

The stimulators could also be powered by ultrasound or infrared light,in which case the energy source would also likely have the disadvantageof having to be placed close to the implant [ABDO A, Sahin M, Freedman DS, Cevik E, Spuhler P S, Unlu M S. Floating light-activatedmicroelectrical stimulators tested in the rat spinal cord. J Neural Eng8(5, 2011):056012, pp. 1-9; GULICK D W, Towe B C. Method of locatingultrasound-powered nerve stimulators. Conf Proc IEEE Eng Med Biol Soc.2012; 2012:887-890].

However, this proximity problem would not occur if the device werepowered by electrochemical energy supplied by the tissue of the patient[MERCIER P P, Lysaght A C, Bandyopadhyay S, Chandrakasan A P, StankovicK M. Energy extraction from the biologic battery in the inner ear. NatBiotechnol 30(12, 2012):1240-1243]. Energy scavenging from othersources, such as body movement, may in principle also be used forautonomous, batteryless powering [E. M. YEATMAN. Advances In PowerSources For Wireless Sensor Nodes. Proceedings of 1st InternationalWorkshop on Body Sensor Networks, London, Apr. 6-7, 2004, pp. 20-21;Joseph A. PARADISO and Thad Starner. Energy Scavenging for Mobile andWireless Electronics. IEEE Pervasive Computing 4(1, 2005):18-27].

Another potential source of scavenged energy is ambientradio waves,e.g., as used in crystal radio sets. However, that potential source isgenerally limited to situations in which very little power is needed forthe device, or the environment contains an unusually high level ofambient electromagnetic energy [E. M. YEATMAN. Advances In Power SourcesFor Wireless Sensor Nodes. Proceedings of 1st International Workshop onBody Sensor Networks, London, Apr. 6-7, 2004, pp. 20-21; Joseph A.PARADISO and Thad Starner. Energy Scavenging for Mobile and WirelessElectronics. IEEE Pervasive Computing 4(1, 2005):18-27; Rick ROBINSON.Air Power: New Device Captures Ambient Electromagnetic Energy to DriveSmall Electronic Devices. Georgia Tech Research News. Research News &Publications Office. Georgia Institute of Technology, 75 Fifth Street,N.W., Suite 314, Atlanta, Ga. 30308, 2011, pp. 1-3; Vikram GUPTA, ArvindKandhalu, Ragunathan (Raj) Rajkumar. Energy Harvesting fromElectromagnetic Energy Radiating from AC Power Lines. Proceedings of the6th Workshop on Hot Topics in Embedded Networked Sensors. Killarney,Ireland, June 2010. Article No. 17, pp. 1-5; Soheil RADIOM, MajidBaghaei-Nejad, Guy Vandenbosch, Li-Rong Zheng, Georges Gielen. Far-fieldRF Powering System for RFID and Implantable Devices with MonolithicallyIntegrated On-Chip Antenna. In: Proc. Radio Frequency IntegratedCircuits Symposium (RFIC), 2010 IEEE, Anaheim, Calif., 23-25 May 2010,pp. 113-116; J. H. HWANG, C. H. Hyoung, K. H. Park and Y. T. Kim. Energyharvesting from ambient electromagnetic wave using human body asantenna. Electronics Letters 49(2, 2013):149-151; MANTIPLY E D, Pohl KR, Poppell S W, Murphy J A. Summary of measured radiofrequency electricand magnetic fields (10 kHz to 30 GHz) in the general and workenvironment. Bioelectromagnetics 18(8, 1997):563-577; FLODERUS B,Stenlund C, Carlgren F. Occupational exposures to high frequencyelectromagnetic fields in the intermediate range (>300 Hz-10 MHz).Bioelectromagnetics 23(8, 2002):568-577].

The proximity problem would also not arise if higher-frequency beamedelectromagnetic waves were used to supply power as now described.Recently, systems have been developed that power implanted pulsegenerators (or their rechargeable battery) using electromagnetic fieldswith frequencies on the order of 300 MHz to 10 GHz. An advantage ofusing these frequencies is that it does not ordinarily require thesource of the fields be in the immediate proximity of the receivingantenna within the implanted device. For example, a horn antenna with awaveguide may be used to direct the radiation from its source to areceiving implant antenna that is several meters away from the horn.Some of these devices may operate either in the inductive mode that wasdescribed in a previous paragraph, or in the higher frequency modewherein the electromagnetic field supplying the stimulator's power ispropagated as a far-field or approximate plane wave [applicationUS20120004708, entitled Implantable medical device and charging systememploying electric fields, to CHEN et al]. Other such devices aredesigned to operate only at the higher frequencies. They may receivepower using a rectenna, or more generally using a dipole, slot, patch,or other type of antenna that can be used to receive power at thesefrequencies [application US20130018438, entitled Far field radiativepowering of implantable medical therapy devices, to CHOW; US20130018439,entitled Implantable nerve wrap for nerve stimulation configured for farfield radiative powering, now U.S. Pat. No. 8,989,867 to CHOW;US20130018440, entitled Powering of an implantable medical therapydelivery device using far field radiative powering at multiplefrequencies, to CHOW].

PERRYMAN et al also disclosed implantable neural stimulators that arepowered by electromagnetic radiation at the higher frequencies,comprising one or more electrodes, a dipole antenna, and stimulationcircuitry, but no internally-supplied power source. Power to thestimulator is supplied through the stimulator's dipole antenna, which isconfigured to receive electrical energy from a second external antenna,using electrical radiative coupling (i.e., coupling to far field orapproximately plane wave radiation). That energy is then used toelectrically stimulate bodily tissue adjacent to the device'selectrodes, such as a peripheral nerve. The device is also configured togenerate a feedback signal, which is sent from the stimulator's dipoleantenna back to the second antenna, also through electrical radiativecoupling. In some embodiments, an intermediate “relay module” isconfigured to generate the actual radiofrequency wave that is receivedby the implanted neural stimulator, for example, with the relay moduleplaced under the skin over the vagus nerve in the neck [WO/2012/138782,entitled Implantable lead, to PERRYMAN et al. US20120283800, entitledNeural Stimulator System, to PERRYMAN et al. US20120330384, entitledRemote control of power or polarity selection for a neural stimulator,to PERRYMAN et al. US20130066400, entitled Microwave field stimulator,to PERRYMAN et al. US20130079849, entitled Relay module for implant, toPERRYMAN et al].

It is understood that implanted devices operating with the higherfrequency electromagnetic radiation may also be used for bidirectionaltelemetry of device parameters or of physiological data, irrespective ofwhether operational power is also supplied by a transmitter operatingwithin those frequencies. For example, telemetry may take place in theMedical Implant Communication Service band (MICS) of 402-405 MHz, andearly implanted telemetry systems with a battery operated withfrequencies of 100 to 500 MHz with a range of about 30 meters [DELGADO JM, Mark V, Sweet W, Ervin F, Weiss G, Bach-Y-Rita G, Hagiwara R.Intracerebral radio stimulation and recording in completely freepatients. J Nery Ment Dis 147(4, 1968):329-340; Eric Y CHOW. Wirelessminiature implantable devices and asics for monitoring, treatment, andstudy of glaucoma and cardiac disease. PhD Dissertation, West Lafayette,Ind.: Purdue University, 2009; Robert PUERS and Jef Thoné. Shortdistance wireless communications. Chapter 7, pp. 219-277. In: H.-J. Yoo,C. van Hoof (eds.), Bio-Medical CMOS ICs. New York:Springer, 2011].

In addition to the need to replace a battery, another disadvantage ofconventional implanted vagus or peripheral nerve stimulation systems isthe mechanical stress and the resulting chronic tissue response causedby the constant movement of tethering electrical cables that areconnected to the pulse generator. Furthermore, the cables may break, andmotion of the cables may cause their attached electrode assemblies tomigrate or rotate, causing the stimulation system to fail. Theseproblems are not unique to vagus nerve stimulators, but occur also withsystems that stimulate other peripheral nerves and the spine [KonstantinV. SLAVIN. Technical Aspects of Peripheral Nerve Stimulation: Hardwareand Complications. pp. 189-202 In: Konstantin V. SLAVIN (ed). PeripheralNerve Stimulation. Progress in Neurological Surgery Vol. 24. Basel(Switzerland): Karger A G, 2011; KIM D D, Vakharyia R, Kroll H R,Shuster A. Rates of lead migration and stimulation loss in spinal cordstimulation: a retrospective comparison of laminotomy versuspercutaneous implantation. Pain Physician 14(6, 2011):513-524]. The samemay be true for the above cited-patent applications that are powered atthe higher electromagnetic frequencies. The application by CHEN usesconventional cables and pulse generators, except that they may bepowered by electromagnetic radiation at the higher frequencies. Anabove-cited application by PERRYMAN et al does not contain a separatepulse generator and tethering cables connected to the electrodeassembly, but it does have a tethered “extension tubing,” with a lumenthat is used with a stylet to facilitate implantation of the stimulator.In one embodiment of their invention, the system's antenna extends intothe tubing [WO/2012/138782, entitled Implantable lead, to PERRYMAN etal]. After the electrodes are implanted, the tubing is shown to be leftin place, and its end is anchored under the skin near the site ofimplant entry. Thus, the system described by PERRYMAN et al. would alsocause tissue response problems, owing to the movement of the tetheringtubing, for the same reason that a tethering electrical cable causesproblems.

Nevertheless, there do exist implanted externally-powered nervestimulation systems that do not contain a tethered lead or tubing afterimplantation. Unfortunately, however, those systems are poweredexternally by inductive coils, not by the higher frequency approximatelyplane wave or far-field electromagnetic radiation. They therefore sufferfrom the disadvantage that an external coil providing energy to theimplanted stimulator must be very close to the implanted pickup coil inorder to transfer energy efficiently. Two such systems are BION devicesand microtransponder devices.

The simplest version of BION stimulators consist of wirelessmicromodules, each of which receives power and command signals byinductive coupling from an external antenna. Its electronic componentsare housed in a hermetically sealed glass capsule, which is 2 mm indiameter×16 mm in length, which is small enough to be implanted througha 12 gauge hypodermic needle. Each device delivers monophasicstimulation pulses through a tantalum capacitor electrode. The laterBION versions contain a rechargeable battery that allows sufficientpower for external programming and advanced telemetry. In that regard,the later BION stimulators resemble miniature stimulators that weredescribed by WHITEHURST et al [LOEB G E, Zamin C J, Schulman J H, TroykP R. Injectable microstimulator for functional electrical stimulation.Med Biol Eng Comput 29(6, 1991):NS13-NS19; CAMERON T, Loeb G E, Peck RA, et al: Micromodular implants to provide electrical stimulation ofparalyzed muscles and limbs. IEEE Trans Biomed Eng 44(9, 1997):781-790;LOEB G E, Richmond F J, Baker L L. The BION devices: injectableinterfaces with peripheral nerves and muscles. Neurosurg Focus 20(5,2006):E2, pp. 1-9; Todd K. WHITEHURST, Joseph H. Schulman, Kristen N.Jaax, and Rafael Carbunaru. The BionMicrostimulator and its ClinicalApplications. pp. 253-273. In: D. D. Zhou, E. Greenbaum (eds.).Implantable Neural Prostheses 1. Devices and Applications. New York,N.Y.:Springer-Verlag, 2009; KANE M J, Breen P P, Quondamatteo F,OLaighin G. BION microstimulators: a case study in the engineering of anelectronic implantable medical device. Med Eng Phys 33(1, 2011):7-16;U.S. Pat. No. 6,735,475, entitled Fully implantable miniatureneurostimulator for stimulation as a therapy for headache and/or facialpain, to WHITEHURST et al]. In one nerve stimulation application, a BIONdevice was found to be comparable in benefit to a noninvasive nervestimulation device, but with the noninvasive device having the advantageof not needing to be implanted [A NESBITT, J Marin, P Goadsby. Treatmentof hemicrania continua by non-invasive vagus nerve stimulation in 2patients previously treated with occipital nerve stimulation. TheJournal of Headache and Pain 1(Suppl 1, 2013):P230].

The BION device was developed in response to a request from the U.S.National Institutes of Health, and another such device was developed byZIAIE and colleagues [ZIAIE B, Nardin M D, Coghlan A R, Najafi K. Asingle-channel implantable microstimulator for functional neuromuscularstimulation. IEEE Trans Biomed Eng 44(10, 1997):909-920; TROYK P R.Injectable electronic identification, monitoring, and stimulationsystems. Annu Rev Biomed Eng 1(1999):177-209]. Subsequently, inductivemicro-stimulators have been developed for additional applications[Rogier A M RECEVEUR, Fred W Lindemans and Nicolaas F de Rooij.Microsystem technologies for implantable applications. Journal ofMicromechanics and Microengineering 17(5, 2007):R50-R80].

Microtransponder devices resemble human-implantableradiofrequency-identification microchips, which are powered inductivelyfrom an external electromagnetic field. They may be joined in arrays anddelivered to the vicinity of a nerve through a hypodermic needle. One oftheir intended applications is the stimulation of a peripheral nerve[U.S. Pat. No. 7,630,771, entitled Grooved electrode and wirelessmicrotransponder system, to CAULLER; US20050137652, entitled System andmethod for interfacing cellular matter with a machine, to CAULLER et al;US20090163889, entitled Biodelivery System for Microtransponder Array,to CAULLER et al; US20120296399, entitled Array of JoinedMicrotransponders for Implantation, to CAULLER et al; ROSELLINI W,Casavant R, Engineer N, Beall P, Pierce D, Jain R, Dougherty P M.Wireless peripheral nerve stimulation increases pain threshold in twoneuropathic rat models. Exp Neurol 235(2, 2012):621-626; Sung-Hoon CHO,Lawrence Cauller, Will Rosellini, and JB Lee, A MEMS-BasedFully-Integrated Wireless neurostimulator, IEEE 23rd InternationalConference on Micro Electro Mechanical Systems (MEMS), 24-28 Jan. 2010,Hong Kong, Proceedings pp. 300-303].

There also exists an implanted, externally-powered nerve stimulationsystem that does not use coils to power the implant, but it contains atethered lead implantation, and it also requires the source of power tobe applied directly to the patient's skin. It works by using a pair ofnoninvasive electrodes applied to the patient's skin to cause currentsto flow under the skin, such that some of this current passes throughelectrical conductors that had been implanted in the vicinity of thenerve that is to be stimulated [Patent application US 20130013041,entitled Implant system and method using implanted passive conductorsfor routing electrical current, now U.S. Pat. No. 8,538,517 toGLUKHOVSKY et al.; Liu Shi G A N, Einat N. Ravid, Jan Kowalczewski,Michel Gauthier, Jaret Olson, Michael Morhart and Arthur Prochazka.First permanent human implant of the Stimulus Router System, a novelneuroprosthesis: preliminary testing of a polarity reversing stimulationtechnique. Conf Proc IEEE Eng Med Biol Soc. 2011:3051-3054; Timothy R.DEER, Jason E. Pope, Matthew Kaplan. A novel method of neurostimulationof the peripheral nervous system: The StimRouter implantable device.Techniques in regional anesthesia and pain management 16(2012):113-117].

To summarize the foregoing background information, one prefers animplanted peripheral nerve stimulator (for example, a vagus nervestimulator) that can be powered using approximately plane wave orfar-field electromagnetic waves with frequencies in the range of 300 MHzto 10 GHz, so that the antenna transmitting energy for the stimulator'selectrodes does not have to be placed in close proximity to theimplanted stimulator in order for the stimulator to receive the energy.A related preference is that the stimulator should have simple circuitryso as to consume a small amount of power, and also so that the externaltransmitter can be a relatively weak power source (either inherently orbecause it is positioned at some distance from the implantedstimulator). One also prefers an implanted stimulator that does not haveattached cables or tubes, the tethering of which would cause chronictissue response due to movement of tethering cables. That is to say, oneprefers a miniature self-contained stimulator that can be powered byexternal GHz plane wave or far-field electromagnetic radiation, withsmall power requirements. Because some such devices could be implantedwith minimally invasive methods, they have additional medical andcosmetic advantages over the implantation of a conventional vagus nervestimulator through open neck surgery. This is because the standardsurgical approach to placement of vagus nerve stimulator electrodes isthrough an incision in the neck, approximately 4 cm in length. Inpatients who have difficulty with keloid and painful scar formation, andfor those patients who are resistant to a neck scar for cosmeticreasons, conventional vagus nerve stimulator therapy has little appeal,regardless of its effectiveness.

The present application discloses methods for solving these problemsthat arise in the design and implantation of a compact, remotely-poweredvagus nerve stimulator. It also discloses new methods for selecting apercutaneous path along which the vagus nerve stimulator is implanted,for performing the implantation with the aid of a robot, for attachingthe implant to surrounding tissue, for repositioning or rotating theimplanted stimulator if that becomes necessary, and for monitoring thesafety and success of the implant procedure.

SUMMARY

The present invention provides systems, apparatus and methods forselectively applying electrical energy to body tissue. In particular,the invention relates to the electrical stimulation of excitable tissue,such as a nerve or nerve ganglion, using devices that are preferablypowered wirelessly. The stimulator uses an adjustable number of fixedvoltage (or fixed current) pulses with fixed duration to elicit desiredchanges in nerve response, the timing of which are controlled by anexternal power transmitter and controller.

In certain embodiments, methods are provided to apply an electricalimpulse to modulate, stimulate, inhibit or block electrical signals innerves within or around the carotid sheath, to acutely treat a conditionor symptom of a patient. In certain preferred embodiments, theelectrical signal may be adapted to reduce, stimulate, inhibit or blockelectrical signals in a vagus nerve to treat many conditions, such ashypotension associated with sepsis or anaphylaxis, hypertension,diabetes, bronchoconstriction, hypovolemic shock, asthma, sepsis,epilepsy, depression, obesity, gastroparesis, anxiety disorders, primaryheadaches, such as migraines or cluster headache, Alzheimer's diseaseand any other ailment affected by vagus nerve transmissions. Suchconditions or symptoms are described in co-pending, commonly assignedpatent applications listed in the section Cross Reference to RelatedApplications, the complete disclosures of which have already beenincorporated herein by reference.

In one aspect of the invention, a stimulation device comprises one ormore electrodes and a pulse generator. The pulse generator is configuredto generate an electrical impulse having a fixed amplitude (either fixedvoltage or fixed current) and a variable duration. The electricalimpulse is applied through the electrodes to excitable tissue, such asnerve or nerve ganglions, to modulate that tissue. In a preferredembodiment, the duration of the electrical impulse is varied by varyinga number of fixed-duration, fixed-amplitude pulses that are appliedwithin each electrical impulse. Varying the number of thesefixed-amplitude pulses allows the stimulation device to apply anelectrical impulse that will cause the nerve to reach its thresholdpotential without varying the amplitude of the electrical impulse.

The stimulator circuit is novel in that it removes one or more elementsfrom conventional stimulators, without sacrificing performance. Inparticular, the present invention removes from conventional designs theability of the stimulator to vary the amplitude of the stimulationpulses. Unexpectedly, one can get substantially the same stimulatoryeffect as that provided by conventional stimulators, by keeping waveformparameters fixed, particularly the amplitude of the electrical impulse,but by then controlling the number and timing of pulses that the nerveexperiences, in order to achieve the same physiologically desirablelevel of nerve stimulation. In essence, this invention uses anadjustable number of fixed voltage (or fixed current) pulses with fixedduration to elicit desired changes in nerve response. These fixedvoltage pulses create one long continuous pulse to the nerve to ensurethat sufficient energy is delivered to the nerve to cause the nerve toreach its action potential and fire. Thus, the present invention reachesthe threshold energy level for a nerve to fire by adjusting the durationof the pulse received by the nerve, rather than adjusting the amplitudeof the pulse.

In another aspect of the invention, the specific number of fixedamplitude pulses that will be delivered to the nerve is preferablydetermined through an iterative process with each patient. Once thesurgeon determines the number of fixed voltage pulses required tostimulate the nerve for a particular patient, this number is programmedinto either the external controller or the implantable stimulator.

In a preferred embodiment, the energy that is used to produce theimpulses is received wirelessly by a dipole or other type of antennathat is also part of the stimulator. The received energy is preferablyfrom far-field or approximately plane wave electromagnetic waves in thefrequency range of about 0.3 to 10 GHz, more preferably about 800 MHz to6 GHz and even more preferably about 800 MHz to 1.2 GHz. In an exemplaryembodiment, the carrier signal is around 915 MHz. The electrical energyis transmitted from the antenna of an external energy source that ispreferably a meter or more outside the patient, but that may also besituated closer or even be placed within the patient. In someembodiments, the transmitter may be worn around the neck as a pendant,placed in a pocket, attached to a belt or watch, or clipped to clothing.The transmitter of wireless power and control signals is preferablyrecharged at a recharging base station that may be positioned remotelyfrom the implanted device, so that patients can sleep without having towear the transmitter, even while the transmission is in progress

The present invention provides an implanted peripheral nerve stimulator,such as a vagus nerve stimulator, that can be powered usingapproximately plane wave or far-field electromagnetic waves withfrequencies in the range of 300 MHz to 10 GHz so that the antennatransmitting energy for the stimulator's electrodes does not have to beplaced in close proximity to the implanted stimulator in order for thestimulator to receive the energy. In addition, the stimulation devicehas relatively simple circuitry so as to consume a small amount ofpower, and also so that the external transmitter can be a relativelyweak power source (either inherently or because it is positioned at somedistance from the implanted stimulator). In particular, the presentinvention is advantageous for vagus nerve stimulation because thestimulation device can be implanted with minimally invasive methods, Forexample, the stimulation device may be implanted through a percutaneouspenetration in the neck.

In preferred embodiments of the present invention, the parameters offixed stimulation pulses are generally as follows. The shape of thepulse is square, sine, triangular or trapezoidal with negative voltagereturn to eliminate DC bias. The electrical impulse will typically havea frequency of between about 1-500 Hz, preferably about 1 to 50 Hz, andmore preferably about 10-35 Hz. In an exemplary embodiment, thefrequency for the impulse received by the nerve is about 25 Hz. Thepreferred fixed voltage received by the nerve is between about 1-20 Vand will typically vary depending on the size and type of electrode andthe distance between the electrode and the nerve. In certain embodimentswhere the nerve is directly attached to the nerve (or implanted adjacentto the nerve), the fixed voltage is preferably about 1 to 4 volts, morepreferably about 2 volts. In other embodiments, wherein the electrodeis, for example, injected into the patient and implanted outside of thesheath, the voltage is preferably between about 7-15 volts and morepreferably about 10 V. In embodiments wherein the current is fixed orheld constant, the preferred fixed current is about 0.5 mA to about 20mA. Similar to voltage, the fixed current will vary depending on thesize and type of electrode and its distance from the nerve. In thoseembodiments where the electrode is adjacent to, or on, the nerve, thecurrent is preferably about 0.5 to 5 mA and more preferably about 3.5mA. In those embodiments, where the electrode is spaced from the nerve(just as an injectable electrode outside of the sheath), the current ispreferably about 7-15 mA and more preferably about 10 mA. The pulseduration is preferably between about 50 to 1000 uS, more preferablyabout 100 to 400 uS and about 200 uS in an exemplary embodiment.

In another aspect of the invention, the stimulator circuit compriseseither a battery or a storage device, such as a capacitor, for storingenergy or charge and then delivering that charge to the circuit toenable the circuit to generate the electrical impulses and deliver thoseimpulses to the electrodes. The energy for the storage device ispreferably wirelessly transmitted to the stimulator circuit through acarrier signal from the external controller. In the preferredembodiments, the energy is delivered to the energy storage devicebetween electrical impulses. Thus, the energy is not being delivered in“real-time”, but during the periods when the pulse is not beingdelivered to the nerve or during the refractory period of the nerve. Forexample, a typical electrical impulse may be ON for about 200 uS andthen OFF for about 39,000 uS. The energy is delivered during this longerOFF time, which enables the system to use a much smaller signal from theexternal generator. The external generator delivers the carrier signalover the OFF period to charge the energy storage device, which thenreleases this energy or charge to the remainder of the circuit todeliver the electrical impulse during the 200 uS ON time. This reducesthe strength of the signal required to deliver the electrical energy tothe storage device within the stimulator circuit because there is alonger period of time to deliver the energy. In addition, it enhancesthe safety of the device because it reduces the risk that uncontrolledenvironmental RF energy will create an electrical connection between thenerve and the charged energy.

In a preferred embodiment, the electrode and signal generator areprimarily, but not exclusively, intended for stimulation of the vagusnerve in the neck, for conditions that include headache, epilepsy,asthma, anxiety/depression, gastric motility disorders, fibromyalgia,Alzheimer's disease, stroke, posttraumatic stress disorder, andtraumatic brain injury. In those applications, the typical signal wouldbe square or sine pulses of fixed amplitude of approximately 10 Volts,where each pulse has a fixed duration of 200 uS. Typically 5 of thesepulses would be produced every 40 mS to produce an effective 25 Hzsignal.

The electrical impulse is sufficient to modulate a selected nerve (e.g.,vagus or one of its branches) at or near the target region to treat acondition or symptom of the patient. The stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of the nerve, to cause the nerve to depolarize and reach athreshold for action potential propagation. By way of example, thethreshold electric field for stimulation of the nerve may be about 8 V/mat 1000 Hz. For example, the device may produce an electric field withinthe patient of about 10 to 600 V/m (preferably less than 100 V/m) and/oran electrical field gradient of greater than 2 V/m/mm. Electric fieldsthat are produced at the vagus nerve are generally sufficient to exciteall myelinated A and B fibers, but not necessarily the unmyelinated Cfibers. However, by using a suitable amplitude of stimulation,excitation of A-delta and B fibers may also be avoided.

The stimulation device may be implanted within a patient by open,endoscopic or minimally invasive methods. In a preferred embodiment, thestimulator is introduced through a percutaneous penetration in thepatient to a target location within, adjacent to, or in close proximitywith, the carotid sheath that contains a vagus nerve. Once in position,electrical impulses are applied through the electrodes of the stimulatorto one or more selected nerves (e.g., vagus nerve or one of itsbranches) to stimulate, block or otherwise modulate the nerve(s) andtreat the patient's condition or a symptom of that condition. For someconditions, the treatment may be acute, meaning that the electricalimpulse immediately begins to interact with one or more nerves toproduce a response in the patient. In some cases, the electrical impulsewill produce a response in the nerve(s) to improve the patient'scondition or symptom in less than 3 hours, preferably less than 1 hourand more preferably less than 15 minutes. For other conditions,intermittent scheduled or as-needed stimulation of the nerve may produceimprovements in the patient over the course of several days or weeks.

A system for implanting the stimulator preferably includes an introducerfor creating percutaneous access to the target region. The introducermay include an access device such as a finder needle for creatingpercutaneous access through a skin surface of the patient's neck, and acannula having an inner lumen for passage of the stimulator therethrough. The access device, e.g. finder needle, is introduced throughthe patient's skin surface in the neck and advanced to a targetlocation, ordinarily near a vagus nerve. The target location may bewithin, directly adjacent to, or in contact with the carotid sheath, orit may be in close proximity with (e.g., within 1-5 mm) of the carotidsheath. The preferred target location, as well as the preferred paththat the finder needle takes to that location, will depend on severalfactors. They include the length of the stimulator and the number of itselectrodes, whether the stimulator's electrodes should produce anelectric field that is intended to have particular directionality,whether deployable anchoring attachments will be used to secure thestimulator to particular surrounding tissue, as well as consideration ofthe electrical waveforms that may be used to preferentially stimulatethe vagus nerve (including the maximum strength or amplitude of thestimulus), the likelihood that the other structures will not be damagedduring the implantation or eventually co-stimulated, and the ease withwhich the finder needle may penetrate and actually follow the intendedpath.

Before deciding the target location and path, ultrasound imaging of thepatient's neck region is performed by the surgeon, preferably in threedimensions and with color flow Doppler in conjunction with microbubblesused as a contrast agent. Objects identified by such imaging wouldpreferably include the vagus nerve and its position within the carotidsheath, large and small blood vessels, cervical sympathetic ganglia, andthe phrenic nerve. Insertion of the finder needle to the target locationalong the preferred anatomical path may be performed by a robotic devicecomprising the finder needle that is positioned under computer controlby actuators, as well as a force sensor and an ultrasound transducerthat provide data used to generate feedback control of the robot.

Once the finder needle is in position, the electrical stimulator isadvanced to the target location and secured in position. In certainembodiments, a cannula or similar device is first advanced to the targetregion, and the electrical stimulator is then directed through thecannula. Insertion of the stimulator to the target location may beaccomplished by forcing tubing attached to the tail of the stimulatorthrough the cannula. Electrical stimulation of the nerve is thenperformed, and tests are made to verify that the stimulator is workingas intended. For example, the patient may be requested to vocalize avowel such as /a/ over several voice ranges (continuous glissando) withand without stimulation. An acoustic analysis of the vocalization may beused to decide whether electrical stimulation of the vagus nerve byelectrodes of the implanted stimulator is in fact having an effect. Inpreferred embodiments, the tubing is then detached from the stimulator,and the tubing and cannula are withdrawn. In some embodiments, anchoringof the stimulator to surrounding tissue is made by deployable springs orby inflatable anchoring attachments. In one embodiment, repositioning ofthe stimulator after it has been implanted may be accomplished with anexternal magnetic field acting on a permanent magnet or soft-magneticmaterial that is part of the stimulator.

In one embodiment, the electrical stimulator comprises an active and areturn electrode located on the stimulator body. In this embodiment, anelectrical impulse is applied across the active and return electrodessuch that the electric current is generally confined within a localspace around the electrical stimulator (i.e., a bipolar electrodeconfiguration), which may be in a particular direction (directed towardsthe nerve) for some electrode configurations.

The novel systems, devices and methods of the present invention are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A is a schematic view of a nerve modulating system (implantablelead module or electrical stimulator) according to one or more aspectsof the present invention.

FIG. 1B is a schematic view of an implantable stimulation deviceaccording to the present invention.

FIG. 1C is a more specific view of the components of one embodiment ofthe implantable stimulation device of FIG. 1B.

FIG. 2A illustrates one embodiment of an electrode assembly in animplantable stimulation device according to the present invention.

FIG. 2B-2F illustrate additional embodiments of electrode assembliesaccording to the present invention.

FIG. 3A-3C illustrates the vertebrae and major vessels of the neck,including the carotid sheath (FIG. 3A), as well as muscles that lie inthe vicinity of those vessels (FIGS. 3B and 3C).

FIG. 4A-4B illustrates the positioning of an ultrasound imagingtransducer that is used to image a vagus nerve in the patient's neck,wherein the transducer is applied to the surface of the neck in thevicinity of the identified anatomical structures (FIG. 4A), thestructural arrangement of which may to vary from individual toindividual as indicated by the percentages shown in FIG. 4B.

FIG. 5A-5C illustrates an exemplary electrical voltage/current profilefor a blocking and/or modulating impulse applied to a portion orportions of a nerve in accordance with an embodiment of the presentinvention (FIG. 5A), wherein the impulses may appear in a pattern ofbursts (FIGS. 5B and 5C).

FIG. 6A-6B illustrates different potential locations and directions forthe introduction of a finder needle into the neck of patient (FIG. 6A),the selection among which may be made according to the patient'sparticular anatomy (FIG. 6B).

FIGS. 7A and 7B illustrate an embodiment of the stimulator that isdesigned to implant electrodes parallel to a nerve by rotating theelectrodes about a hinge, as well as to anchor the stimulator tostructures within the patient's neck, in which anchoring ribbon springsthat had been folded against tubing are released in order to hugsurrounding tissue.

FIGS. 8A and 8B illustrates an embodiment of the stimulator that isdesigned to be implanted parallel to a nerve and to anchor thestimulator to structures within the patient's neck, comprising ananchoring ribbon spring that is initially coiled around tubing beforebeing released in order to hug surrounding tissue.

FIG. 9A-9B illustrates a robotic device for the introduction of a finderneedle into the neck of a patient (FIG. 9A), the automatic control ofwhich involves processing of ultrasound images and the analysis of dataproduced by force and position sensors (FIG. 9B).

FIG. 10 illustrates an introducer according to one embodiment of thepresent invention, which is advanced through a percutaneous penetrationin a patient to the target region near the carotid sheath.

FIG. 11 illustrates an electrode assembly like the one shown in FIG. 2Cas it is advanced into and through the introducer to the target regionin the patient.

FIG. 12 illustrates the use and removal of a cannula that may be used tofacilitate introduction of the stimulator into the neck of the patient.

DETAILED DESCRIPTION

In one or more embodiments of the present invention, electrical energyis applied in a patient to a target region within or around the carotidsheath (also called the carotid neurovascular bundle) to treat apatient's ailment. The invention is particularly useful for applyingelectrical impulses that ultimately interact with the signals of a vagusnerve, which lies within the carotid sheath, to achieve a therapeuticresult. The nerve stimulation may result in benefits to the patient suchas: relaxation of the smooth muscle of the bronchia, increase in bloodpressure associated with orthostatic hypotension, reduction in bloodpressure, treatment of epilepsy, treating ileus conditions, depression,anaphylaxis, obesity, a neurodegenerative disorder such as Alzheimer'sdisease, migraine and other types of headache, rhinitis, sinusitis,asthma, atrial fibrillation, autism, gastroparesis and other functionalgastrointestinal disorders, and/or any other ailment that may beaffected by nerve transmissions of a vagus nerve. Such treatments fordifferent disorders are disclosed in the commonly-assigned applicationsthat are listed in the section Cross Reference to Related Applicationsof this disclosure.

The fact that electrical stimulation of a vagus nerve can be used totreat so many disorders may be understood as follows. The vagus nerve iscomposed of motor and sensory fibers. The vagus nerve leaves thecranium, passes down the neck within the carotid sheath to the root ofthe neck, then passes to the chest and abdomen, where it contributes tothe innervation of the viscera. A human vagus nerve (tenth cranialnerve, paired left and right) consists of over 100,000 nerve fibers(axons), mostly organized into groups. The groups are contained withinfascicles of varying sizes, which branch and converge along the nerve.Under normal physiological conditions, each fiber conducts electricalimpulses only in one direction, which is defined to be the orthodromicdirection, and which is opposite the antidromic direction. However,external electrical stimulation of the nerve may produce actionpotentials that propagate in orthodromic and antidromic directions.Besides efferent output fibers that convey signals to the various organsin the body from the central nervous system, the vagus nerve conveyssensory (afferent) information about the state of the body's organs backto the central nervous system. Some 80-90% of the nerve fibers in thevagus nerve are afferent (sensory) nerves, communicating the state ofthe viscera to the central nervous system.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia, which take the form of swellingsnear the base of the skull. Vagal afferents traverse the brainstem inthe solitary tract, with some eighty percent of the terminating synapsesbeing located in the nucleus of the tractus solitarius (or nucleustractus solitarii, nucleus tractus solitarius, or NTS). The NTS projectsto a wide variety of structures in the central nervous system, such asthe amygdala, raphe nuclei, periaqueductal gray, nucleusparagigantocellurlais, olfactory tubercule, locus ceruleus, nucleusambiguus and the hypothalamus. The NTS also projects to the parabrachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insula, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions [JEAN A. The nucleustractus solitarius: neuroanatomic, neurochemical and functional aspects.Arch Int Physiol Biochim Biophys 99(5, 1991):A3-A52]. Thus, stimulationof vagal afferents can modulate the activity of many structures of thebrain and brainstem through these projections.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections controls parasympathetic function primarilybelow the level of the diaphragm, while the ventral vagal complex,comprised of nucleus ambiguus and nucleus retrofacial, controlsfunctions primarily above the diaphragm in organs such as the heart,thymus and lungs, as well as other glands and tissues of the neck andupper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus, which is relevant to potential cardiovascular sideeffects that may be produced by vagus nerve stimulation.

The vagus efferent fibers innervate parasympathetic ganglionic neuronsthat are located in or adjacent to each target organ. The vagalparasympathetic tone resulting from the activity of these fibers isbalanced reflexly in part by sympathetic innervations. Consequently,electrical stimulation of a vagus nerve may result not only inmodulation of parasympathetic activity in postganglionic nerve fibers,but also a reflex modulation of sympathetic activity. The ability of avagus nerve to bring about widespread changes in autonomic activity,either directly through modulation of vagal efferent nerves, orindirectly via activation of brainstem and brain functions that arebrought about by electrical stimulation of vagal afferent nerves,accounts for the fact that vagus nerve stimulation can treat manydifferent medical conditions in many end organs. Selective treatment ofparticular conditions is possible because the parameters of theelectrical stimulation (frequency, amplitude, pulse width, etc.) mayselectively activate or modulate the activity of particular afferent orefferent A, B, and/or C fibers that result in a particular physiologicalresponse in each individual.

As ordinarily practiced, the electrodes used to stimulate a vagus nerveare implanted about the nerve during open neck surgery. For manypatients, this may be done with the objective of implanting permanentelectrodes to treat epilepsy, depression, or other conditions [Arun PaulAMAR, Michael L. Levy, Charles Y. Liu and Michael L. J. Apuzzo. Chapter50. Vagus nerve stimulation. pp. 625-638, particularly 634-635. In:Elliot S. Krames, P. Hunber Peckham, Ali R. Rezai, eds. Neuromodulation.London: Academic Press, 2009; KIRSE D J, Werle A H, Murphy J V, Eyen TP, Bruegger D E, Hornig G W, Torkelson R D. Vagus nerve stimulatorimplantation in children. Arch Otolaryngol Head Neck Surg 128(11,2002):1263-1268]. In that case, the electrode is often a spiralelectrode, although other designs may be used as well [U.S. Pat. No.4,979,511, entitled Strain relief tether for implantable electrode, toTERRY, Jr.; U.S. Pat. No. 5,095,905, entitled Implantable neuralelectrode, to KLEPINSKI]. In other patients, a vagus nerve iselectrically stimulated during open-neck thyroid surgery in order toconfirm that the nerve has not been accidentally damaged during thesurgery. In that case, a vagus nerve in the neck is surgically exposed,and a temporary stimulation electrode is clipped about the nerve[SCHNEIDER R, Randolph G W, Sekulla C, Phelan E, Thanh P N, Bucher M,Machens A, Dralle H, Lorenz K. Continuous intraoperative vagus nervestimulation for identification of imminent recurrent laryngeal nerveinjury. Head Neck. 2012 Nov. 20. doi: 10.1002/hed.23187 (Epub ahead ofprint, pp. 1-8)].

In a commonly assigned, copending application, Applicant disclosed thatit is also possible to electrically stimulate a vagus nerve using aminimally invasive surgical approach, namely percutaneous nervestimulation. In that procedure, a pair of electrodes (an active and areturn electrode) are introduced through the skin of a patient's neck tothe vicinity of a vagus nerve, and wires connected to the electrodesextend out of the patient's skin to a pulse generator [Publicationnumber US20100241188, entitled Percutaneous electrical treatment oftissue, to J. P. ERRICO et al.; SEPULVEDA P, Bohill G, Hoffmann T J.Treatment of asthmatic bronchoconstriction by percutaneous low voltagevagal nerve stimulation: case report. Internet J Asthma Allergy Immunol7(2009):e1 (pp1-6); MINER, J. R., Lewis, L. M., Mosnaim, G. S., Varon,J., Theodoro, D. Hoffman, T. J. Feasibility of percutaneous vagus nervestimulation for the treatment of acute asthma exacerbations. Acad EmergMed 2012; 19: 421-429].

Percutaneous nerve stimulation procedures had previously been describedprimarily for the treatment of pain, but not for a vagus nerve, which isordinarily not considered to produce pain and which presents specialchallenges [HUNTOON M A, Hoelzer B C, Burgher A H, Hurdle M F, Huntoon EA. Feasibility of ultrasound-guided percutaneous placement of peripheralnerve stimulation electrodes and anchoring during simulated movement:part two, upper extremity. Reg Anesth Pain Med 33(6, 2008):558-565; CHANI, Brown A R, Park K, Winfree C J. Ultrasound-guided, percutaneousperipheral nerve stimulation: technical note. Neurosurgery 67(3 SupplOperative, 2010):ons136-139; MONTI E. Peripheral nerve stimulation: apercutaneous minimally invasive approach. Neuromodulation 7(3,2004):193-196; Konstantin V SLAVIN. Peripheral nerve stimulation forneuropathic pain. US Neurology 7(2, 2011):144-148].

In the present invention, electrodes are preferably also introducedpercutaneously to the vicinity of a vagus nerve, but unlike the previousminimally invasive disclosure, the electrodes are not ultimatelyconnected to wires that extend outside the patient's skin. Instead, inthe present invention, the percutaneously implanted stimulator receivesenergy wirelessly from an external transmitter that need not be in closeproximity to the skin of the patient, and electrical pulse generationoccurs within the implanted stimulator using that energy.

As shown in FIG. 1A, the nerve modulating device 300 of the presentinvention (also known as an implantable lead module or simply anelectrical nerve stimulator) is powered by the receipt of far-field orapproximately plane wave electromagnetic energy with frequencies in therange of 0.3 to 10 GHz (preferably about 800 MHz to about 6 GHz, andmore preferably about 800 MHz to about 1.2 MHz) which is receivedwirelessly by an antenna 360 within, or attached to, the device 300. Theenergy that powers the nerve modulating device 300 is transmitted by anexternal device, which in FIG. 1A is labeled as a Controller 370.Controller 370 is in turn controlled by a programmer device 380, whichpreferably communicates with controller 370 wirelessly. In operation,the nerve modulating device 300 is implanted within the patient, thecontroller 370 may be either outside of the patient or implanted withinthe patient, and the programmer 380 is operated manually by the patientor a caregiver. The antenna of the controller 370 is activelytuned/matched to the resonant frequency of antenna in the implanteddevice 300 so that the maximum efficiency of power transmission isachieved. There may be several antennae at various orientations in theexternal unit and/or in the implanted signal generator to enhancecoupling efficiency in various orientations. The unit 370 supplyingpower and control to the implanted device 300 could be AC powered and/orbattery powered. If powered by rechargeable batteries, a battery chargermay be an accessory to the system. The controller 370 is preferably bothportable and rechargeable. In one embodiment, it may be worn around theneck as a pendant, placed in a pocket, or clipped to clothing. Thiswireless transmitter 370 is preferably recharged at a recharging baseand has a significant range of transmission, preferably up to four feet,so that patients can sleep without having to wear the transmitter.

FIG. 1B is a more detailed schematic diagram of the nerve modulatingdevice 300 for delivering electrical impulses to nerves. As shown,device 300 comprises an electrical impulse generator 310; a power source320 coupled to the electrical impulse generator 310; a control unit 330in communication with the electrical impulse generator 310 and coupledto the power source 320; and one or more electrodes 340 coupled to theelectrical impulse generator 310. Nerve modulating device 300 isconfigured to generate electrical impulses sufficient to modulate theactivity of one or more selected regions of a nerve (not shown). Thepower source 320 receives energy wirelessly via an antenna 360, whereinthe energy is in the form of far-field or approximately plane-waveelectromagnetic waves with frequencies in the range of 0.3 to 10 GHz,preferably about 800 MHz to about 1.2 MHz.

The control unit 330 may control the electrical impulse generator 310for generation of a signal suitable for amelioration of a patient'scondition when the signal is applied via the electrodes 340 to thenerve. It is noted that nerve modulating device 300 excluding theelectrodes 340 may be referred to by its function as a pulse generator.U.S. Pat. No. 7,418,292 and U.S. Patent Application Publication2005/0075702, both to SHAFER, both of which are incorporated herein byreference, relating to stimulation of neurons of the sympathetic nervoussystem to attenuate an immune response, contain descriptions of pulsegenerators that may be applicable to various embodiments of the presentinvention.

FIG. 1C illustrates one embodiment of the nerve modulating device 300that consumes relatively little power and may therefore receive powerfrom a correspondingly weak and/or distant external transmitter. Toachieve low power consumption, the embodiment is designed to use aminimum of components. This may be accomplished by designing the deviceto produce constant voltage pulses, rather than constant current pulses,because circuits for the latter are more complex and consume more powerthan the former. However, for some patients a constant current pulse maybe preferred, depending on the detailed anatomy of the patient's neck inthe vicinity of the stimulated nerve (see below and FIG. 4).Consequently, constant current pulses are also contemplated by theinvention [DELIMA, J. A. and Cordeiro, A. S. A simple constant-currentneural stimulator with accurate pulse-amplitude control. Engineering inMedicine and Biology Society, 2001. Proceedings of the 23rd AnnualInternational Conference of the IEEE (Vol. 2, 2001) 1328-1331]. Ineither case, simplicity of circuit design is provided by a design thatmakes the amplitude of the pulse constant, rather than by allowing theamplitude to be variable. Accordingly, the present invention modulatesthe stimulation power to the nerve by altering the number and timing ofthe pulses, rather than by modulating the amplitude of individualpulses. Additional simplicity of design may be achieved by usingcommunication that occurs in one direction only, from the transmitter tothe stimulator (simplex communication according to the ANSI definition,rather than half or full duplex communication).

The stimulator circuit is novel in that it removes one (or more)elements from conventional stimulators, without sacrificing performance.In particular, the present invention removes from conventional designsthe ability of the stimulator to vary the amplitude of the stimulationpulses. Unexpectedly, one can get substantially the same stimulatoryeffect as that provided by conventional stimulators, by keeping waveformparameters fixed, particularly the amplitude of pulses, but by thencontrolling the number and timing of pulses that the nerve experiences,in order to achieve the same physiologically desirable level of nervestimulation. In essence, this invention uses an adjustable number offixed voltage (or fixed current) pulses with fixed duration to elicitdesired changes in nerve response. These fixed voltage pulses create onelong continuous pulse to the nerve to ensure that sufficient energy isdelivered to the nerve to cause the nerve to reach its action potentialand fire. Thus, the present invention reaches the threshold energy levelfor a nerve to fire by adjusting the duration of the pulse received bythe nerve, rather than adjusting the amplitude of the pulse.

In another aspect of the invention, the specific number of fixedamplitude pulses that will be delivered to the nerve is preferablydetermined through an iterative process with each patient. Once thesurgeon determines the number of fixed voltage pulses required tostimulate the nerve for a particular patient, this number is programmedinto either the external controller or the implantable stimulator.

A constant-voltage pulse design teaches against prevailing preferreddesigns for vagus nerve stimulators. Thus, constant-voltage pulses areused in cardiac pacemakers, deep brain stimulation, and some implantableneuromodulators for treatment of incontinence and chronic pain, butconstant-current pulses are used for cochlear implants and vagus nervestimulators [D. PRUTCHI and M. Norris Stimulation of excitable tissues.Chapter 7, pp. 305-368. In: Design and development of medical electronicinstrumentation. Hoboken: John Wiley & Sons, 2005]. In the latterapplications, the constant current design is said to be preferredbecauses light variations in stimulator-to-nerve distance change theability of the constant-voltage pulse stimulator to depolarize thenerve, which is less of a problem with constant-current pulsestimulators. With the constant current design, the stimulationthresholds stay more or less constant even with changing electrodeimpedance and in growth of tissue into the neural interface[Emarit RANU.Electronics. Chapter 10, pp. 213-243. In:Jeffrey E. Arle, Jay L.Shils(eds). Essential Neuromodulation. Amsterdam, Boston: AcademicPress. 2011]. For example, the BION stimulators described in thebackground section of the present application generate only constantcurrent pulses.

In some embodiments of the present invention, a constant voltage pulseis used because it can be produced with a simpler circuit that consumesless power, as compared with constant pulse current circuits. Theabove-mentioned potential problem with variation in stimulator-to-nervedistance is addressed by anchoring the stimulator to the vagus nerve(see FIGS. 7 and 8). Furthermore, the problem may be circumvented tosome extent in the present invention by coating the stimulator'selectrodes with a very thin layer of poorly conducting material. This isbecause the presence of a poorly conducting boundary layer surroundingthe stimulator minimizes the differential effects of conductivityvariations and electrode location during constant current and constantvoltage stimulation[Mark M. STECKER. Nerve stimulation with an electrodeof finite size: differences between constant current and constantvoltage stimulation. Computers in Biology and Medicine 34(2004):51-94].

Additional circuit simplicity and minimized power requirements areaccomplished in the embodiment shown in FIG. 1C by fixing thecharacteristics of the stimulation pulses, rather than by addingcircuits that would allow the characteristics to be adjusted through useof external control signals. For example, the output pulses shown inFIG. 1C are shown to be generated using a pair of monostablemultivibrators. The first multivibrator receives a trigger pulse fromthe control unit 330, resulting in a pulse of fixed duration. The secondmultivibrator is triggered by the falling edge of the firstmultivibrator's pulse, and the pair of pulses from the twomultivibrators are combined with suitable polarity using a differentialoperational amplifier. Thus, in this example, the impulse generator 310consists of the multivibrators and operational amplifier. The amplifierin turn presents the stimulation pulses to the electrodes 340. The timeperiod that a monostable multivibrator remains in its unstable state(the pulse width) is a function of its component resistor and capacitorvalues, so if the pulse width can be preselected for a patient, thedevice can be designed using correspondingly fixed R and C values. Onthe other hand, if a variable pulse width is needed during preliminarytesting with a patient, the multivibrator circuit can be made morecomplex, with the pulse width selected on the basis of coded signalsthat are transmitted to the impulse generator 310 via the control unit330. Once the appropriate pulse width has been selected, a controlsignal may be sent from the control unit 330 to disable extraneous powerconsumption by the variable pulse-width circuitry. Proper pulse width isparticularly important in stimulating nerve fibers having theappropriate diameters [see discussion below and SZLAVIK R B, de Bruin H.The effect of stimulus current pulse width on nerve fiber sizerecruitment patterns. Med Eng Phys 21(6-7, 1999):507-515].

It is also understood that more complex pulses may also be preferred, asillustrated below in FIG. 5, which would require a correspondingly morecomplex circuitry and possibly additional power consumption, as comparedwith the circuit shown in FIG. 1C [JEZERNIK S, Morari M. Energy-optimalelectrical excitation of nerve fibers. IEEE Trans Biomed Eng 52(4,2005):740-743; Wongsarnpigoon A, Woock J P, Grill W M. Efficiencyanalysis of waveform shape for electrical excitation of nerve fibers.IEEE Trans Neural Syst Rehabil Eng 18(3, 2010):319-328; FOUTZ T J,Ackermann D M Jr, Kilgore K L, McIntyre C C (2012) Energy efficientneural stimulation: coupling circuit design and membrane biophysics.PLoS

ONE 7(12): e51901. doi:10.1371/journal.pone.0051901, pp. 1-8; McLEOD KJ, Lovely D F, Scott R N. A biphasic pulse burst generator for afferentnerve stimulation. Med Biol Eng Comput 25(1, 1987):77-80].

The control unit 330 in FIG. 1C is shown to exercise its control only bypresenting trigger pulses to the impulse generator 310. In this example,the train of pulses appearing across the electrodes 340 is determinedonly by the timing of the sequence of trigger pulses. The trigger pulsesare themselves encoded in the signal that is transmitted from controller370 in FIG. 1A, shown in FIG. 1C as “RF signal with encoded triggerpulse.” The trigger pulses are extracted and reconstructed from thetransmitted signal by an RF demodulator in the control unit 330. Thereare many methods for transmitting and decoding such control signals, andthe present invention may be designed to use any of them [Robert PUERSand Jef Thoné. Short distance wireless communications. Chapter 7, pp.219-277, In: H.-J. Yoo, C. van Hoof (eds.), Bio-Medical CMOS ICs. NewYork:Springer, 2011]. Because the timing of pulses is determined by thetrigger pulses emanating from the transmitted signal, the circuit shownin FIG. 1C does not even need a clock, thereby reducing its powerrequirements. However, in other embodiments a clock may be included aspart of the timing circuitry. It is understood that in order to commanda pulse of the treatment signal and switch that pulse to the electrodes,it is possible to use a control RF signal having a different frequencythan the one used to provide power, or encode the command based onvariation in the RF signal's amplitude, pulse width and/or duration.

The transmitted RF signal is received by an antenna 360, and the signalprovides power for the stimulation device 300, in addition to thecontrol signals. The power is provided by the power source 320 in FIG.1C. As shown there, energy from the transmitted RF signal (beamed power)is accumulated in a storage capacitor, which is eventually discharged inconjunction with the creation of stimulation pulses that are applied tothe electrodes 340. In addition to the beamed power, there may also bescavenged power, which arises from the reception of ambientelectromagnetic radiation by the antenna 360. Special circuits andantennas may be used to scavenge such ambient electromagnetic radiation[Soheil RADIOM, Majid Baghaei-Nejad, Guy Vandenbosch, Li-Rong Zheng,Georges Gielen. Far-field RF Powering System for RFID and ImplantableDevices with Monolithically Integrated On-Chip Antenna. In: Proc. RadioFrequency Integrated Circuits Symposium (RFIC), 2010 IEEE, Anaheim,Calif., 23-25 May 2010, pp. 113-116]. Power scavenging may be mostappropriate in a hospital setting where there is significant ambientelectromagnetic radiation, due to the use thereof diathermy units andthe like [FLODERUS B, Stenlund C, Carlgren F. Occupational exposures tohigh frequency electromagnetic fields in the intermediate range (>300Hz-10 MHz). Bioelectromagnetics 23(8, 2002):568-577].

The stimulator circuit comprises either a battery or a storage device,such as a capacitor, for storing energy or charge and then deliveringthat charge to the circuit to enable the circuit to generate theelectrical impulses and deliver those impulses to the electrodes. Theenergy for the storage device is preferably wirelessly transmitted tothe stimulator circuit through a carrier signal from the externalcontroller. In the preferred embodiments, the energy is delivered to theenergy storage device between electrical impulses. Thus, the energy isnot being delivered in “real-time”, but during the periods when thepulse is not being delivered to the nerve or during the refractoryperiod of the nerve. For example, a typical electrical impulse may be ONfor about 200 uS and then OFF for about 39,000 uS. The energy isdelivered during this longer OFF time, which enables the system to use amuch smaller signal from the external generator. The external generatordelivers the carrier signal over the OFF period to charge the energystorage device, which then releases this energy or charge to theremainder of the circuit to deliver the electrical impulse during the200 uS ON time.

Transmitting energy to the storage device in between the electricalimpulses provides a number of advantages. First, it increase the lengthof time that the electrical energy can be delivered to charge thestorage device. This reduces the strength of the signal required todeliver the electrical energy to the storage device, thereby reducingthe overall power requirements of the external controller and reducingthe complexity of the stimulator circuitry. In addition, it enhances thesafety of the device because it reduces the risk that uncontrolledenvironmental RF energy will create an electrical connection between thenerve and the charged energy. Since the storage device is receivingelectrical energy between electrical impulses, there is no electricalconnection between the stimulator circuit and the nerve as the storagedevice is charged. This reduces the risk of the electrical energy beingaccidentally applied to the nerve.

In order to power the impulse generator and demodulation circuits, thepower source 320 in FIG. 1C makes use of a voltage regulator, the outputfrom which is a stable voltage V. The circuits that may be selected forthe voltage regulator comprise those described by BOYLESTAD [Robert LBOYLESTAD and Louis Nashelsky. Power Supplies (Voltage Regulators).Chapter 18, pp. 859-888. In: Electronic devices and circuit theory, 8thed. Upper Saddle River, N.J.: Prentice Hall, 2002]

In preferred embodiments of the present invention, the parameters offixed stimulation pulses are generally as follows. The shape of thepulse is square, sine, triangular or trapezoidal with negative voltagereturn to eliminate DC bias. The electrical impulse will typically havea frequency of between about 1-500 Hz, preferably about 1 to 50 Hz, andmore preferably about 10-35 Hz. In an exemplary embodiment, thefrequency for the impulse received by the nerve is about 25 Hz. Thepreferred fixed voltage received by the nerve is between about 1-20 Vand will typically vary depending on the size and type of electrode andthe distance between the electrode and the nerve. In certain embodimentswhere the nerve is directly attached to the nerve (or implanted adjacentto the nerve), the fixed voltage is preferably about 1 to 4 volts, morepreferably about 2 volts. In other embodiments, wherein the electrodeis, for example, injected into the patient and implanted outside of thesheath, the voltage is preferably between about 7-15 volts and morepreferably about 10 V. In embodiments wherein the current is fixed orheld constant, the preferred fixed current is about 0.5 mA to about 20mA. Similar to voltage, the fixed current will vary depending on thesize and type of electrode and its distance from the nerve. In thoseembodiments where the electrode is adjacent to, or on, the nerve, thecurrent is preferably about 0.5 to 5 mA and more preferably about 3.5mA. In those embodiments, where the electrode is spaced from the nerve(just as an injectable electrode outside of the sheath), the current ispreferably about 7-15 mA and more preferably about 10 mA. The pulseduration is preferably between about 50 to 1000 uS.

Benefits of the disclosed system include the following features. Theimplanted signal generator can be much smaller than a traditionalimplanted generator. The surgery to implant this system can be doneunder local anesthesia on an outpatient basis in a non-hospital settingresulting in faster recovery and less scarring. Furthermore, since thereis no implanted battery, the patient does not need additional surgeriesto replace batteries, which is especially important if the patient has atreatment protocol that requires treatments involving significant powerand duration. Also, the limited circuitry implanted in the body will bemore reliable than traditional implanted generators. Because thetreatment is powered and controlled from outside the body, changes tothe treatment protocol can be made quickly and easily. In the event ofan emergency, the patient or caregiver can quickly turn-off or removethe power/control unit to stop treatment.

The stimulator circuit is novel in that it removes one (or more)elements from conventional stimulators, without sacrificing performance.In particular, the present invention removes from conventional designsthe ability of the stimulator to vary the amplitude of the stimulationpulses. Unexpectedly, one can get substantially the same stimulatoryeffect as that provided by conventional stimulators, by keeping waveformparameters fixed, particularly the amplitude of pulses, but by thencontrolling the number and timing of pulses that the nerve experiences,in order to achieve the same physiologically desirable level of nervestimulation. In essence, this invention is using an adjustable number offixed voltage (or current) pulses with fixed duration to elicit desiredchanges in nerve response.

The electrode and signal generator are primarily, but not exclusively,intended for stimulation of the vagus nerve in the neck, for conditionsthat include headache, epilepsy, asthma, anxiety/depression, gastricmotility disorders, fibromyalgia, Alzheimer's disease, stroke,posttraumatic stress disorder, and traumatic brain injury. In thoseapplications, the typical signal would be square or sine pulses of fixedamplitude approximately 2 Volts, where each pulse has a fixed durationof 200 uS. Typically 5 of these pulses would be produced every 40 mS toproduce an effective 25 Hz signal. The selection of these waveformparameters is discussed more fully below.

Although the preferred embodiments of the invention are as describedabove, it is understood that one may also modify the capabilities of thedevice as follows. Optionally, the pulse command could have an addressor other identifier associated with it so that only a particular signalgenerator would be activated. This would allow a patient to havemultiple implanted signal generators in the body with each responding toits own command from the same or multiple power/control units. Anotheroption would be to have circuitry or a processor in the implanted signalgenerator that could communicate a signal back to the power/controlunit. This signal could contain status information such as voltage,current, number of pulses applied or other applicable data. The antennaeand RF signals in this system could also be replaced by closely coupledcoils of wire and lower frequency signals that are inductively coupledthrough the body.

No previous study has documented a need for more than a simple dipoleconfiguration for percutaneous nerve stimulation, i.e., a configurationconsisting of an electrode pair—a return and active electrode.Accordingly, the electrodes 340 in FIG. 1B may in one embodiment besimply such an electrode pair. Preferably, the pair of electrodes willbe oriented parallel to the nerve, but a perpendicular (transverse)placement of the two electrodes in relation to the nerve might alsoprovide acceptable stimulation [HUNTOON M A, Hoelzer B C, Burgher A H,Hurdle M F, Huntoon E A. Feasibility of ultrasound-guided percutaneousplacement of peripheral nerve stimulation electrodes and anchoringduring simulated movement: part two, upper extremity. Reg Anesth PainMed 33(6, 2008):558-565].

Nevertheless, some investigators have adopted the use of threeelectrodes to stimulate a vagus nerve during surgical monitoring, on thegrounds that stray currents are thereby minimized [V3 Vagus Electrode.Inomed North America. 453 Washington Street Suite 5A. Boston, Mass.02111; LAMADE W, Ulmer C, Seimer A, et al. A new system for continuousrecurrent laryngeal nerve monitoring. Minim Invasive Ther AlliedTechnol16(2007):149-154; LAMADE W, Ulmer C, Rieber F, Friedrich C, Koch K P,Thon K P. New backstrap vagus electrode for continuous intraoperativeneuromonitoring in thyroid surgery. Surg Innov 18(3, 2011):206-213; W.LAMADE, C. Ulmer, C. Friedrich, F. Rieber, K. Schymik, H. M. Gemkow, K.P. Koch, T. Göttsche, K. P. Thon. Signalstabilität alsGrundvoraussetzung für kontinuierliches intraoperatives Neuromonitoring(Signal stability as key requirement for continuous intraoperativeneuromonitoring). Chirurg 82(2011):913-920]. Accordingly, the electrodes340 in FIG. 1B may in one embodiment comprise three electrodes.

Stimulation devices containing four or more electrodes are alsocontemplated by the invention. Such an electrode configuration wouldresemble the ones used for spinal cord stimulation, which providerectangular, biphasic, charge-balanced pulses of adjustable rate andduration to each electrode. When used with a conventional pulsegenerator for such devices, all electrode contacts connected as anodeswill have the same voltage, and all electrode contacts connected ascathodes will have the same voltage. Unipolar stimulation can be appliedonly if the device were to be connected with an insulated wire to areturn electrode that is located distantly near the surface of thepatient's skin. Thus, for devices containing four or more electrodes,each electrode is conventionally programmed to have one of three states:disconnected, anode, or cathode [DE VOS CC, Hilgerink M P, Buschman H P,Holsheimer J. Electrode contact configuration and energy consumption inspinal cord stimulation. Neurosurgery 65(6 Suppl, 2009):210-216].

For a device containing 16 or 32 electrodes, the number of possibleprogrammed states is very large, in which case, the selection of theprogrammed state is preferably done by computer simulation [HOLSHEIMERJ. Computer modelling of spinal cord stimulation and its contribution totherapeutic efficacy. Spinal Cord 36(8, 1998):531-540]. For the presentinvention, such computer modeling would incorporate knowledge of theelectrical properties of the vagus nerve and its surrounding tissue.Pulse width is usually set to between 100 to 400 microseconds, but forsuch modeling, the pulse width is also a variable, which affects thearea of coverage [LEE D, Hershey B, Bradley K, Yearwood T. Predictedeffects of pulse width programming in spinal cord stimulation: amathematical modeling study. Med Biol Eng Comput 49(7, 2011):765-774].The result of the simulation is a set of programming options, selectedto preferentially stimulate the nerve in a preselected target volume.After an initial electrode configuration is selected, the configurationmay be reprogrammed to optimize its effectiveness, even after the deviceis implanted in the patient [MANOLA L, Holsheimer J, Veltink P H,Bradley K, Peterson D. Theoretical investigation into longitudinalcathodal field steering in spinal cord stimulation. Neuromodulation (2,2007):120-132].

The invention also contemplates an electrode configuration in which allelectrode contacts connected as anodes may have a different voltage, andall electrode contacts connected as cathodes may have a differentvoltage. For the electrodes implanted parallel to the vagus nerve, thismay occur when the anode and cathode voltages for different electrodeschange rapidly in sequence from one end of the device to the other, inan attempt to entrain or inhibit action potentials of certain fibers ofthe nerve bundle. This may be done, for example, so as to stimulateparticular afferent versus efferent fibers. In this example, thetemporal sequence of electrode activation by the device may be in theorthodromic or antidromic direction for any particular fiber within thevagus nerve.

FIG. 2 illustrates different electrode assemblies that are contemplatedby the invention. The assemblies shown as FIG. 2A and 2B are adaptedfrom the disclosure of PERRYMAN et al [WO/2012/138782, entitledImplantable lead, to PERRYMAN et al], which describes how the devicecontains a dipole antenna for the receipt of externally transmittedenergy, as well as electronic components for the generation ofelectrical stimulation pulses through the electrodes. In FIG. 2A, themodulating device 300 comprises four electrodes 340 that are separatedand surrounded by electrically insulating material 205. As shown, thedevice has the style of a paddle, so that the stimulation occurspreferentially on the side of the paddle with exposed electrodes 340.The device has attached extension tubing 201 with a central lumen 204that is intended for the introduction of a stylet or other tool usedduring implantation of the device 300. In FIG. 2B, the modulating device300 comprises eight electrodes 340 that are separated by electricallyinsulating material 205. The device also has attached extension tubing201 with a central lumen 204. As shown, the device in FIG. 2B has thestyle of a cylinder, so that stimulation from the exposed electrodes 340occurs symmetrically with respect to the axis of the cylinder.

Unlike the disclosure by PERRYMAN et al, the present inventioncontemplates removal of the extension tubing 201 after implantation ofthe device 300. This may be performed by introducing a cutting tool intothe lumen 204 of the tubing 201, then cutting through the tubing alongits perimeter to separate the tubing from the device 300. The tubing isthen withdrawn slightly to permit anchoring of the device 300, e.g., byinjection of surgical glue through the lumen 204 about the tail ofdevice 300. Then, the tubing 201 is completely withdrawn from thepatient, leaving the device 300 at its implantation site. However,preferred methods for separating the device 300 from the tubing 201 areillustrated in connection with FIG. 2C, and other methods for anchoringthe device to surrounding tissue are disclosed below.

The length of device 300 (without tubing) must be sufficient toaccommodate the number of electrodes 340 that it houses. The devicelength is also generally proportional to the length of its dipoleantenna that is used to receive the electromagnetic energy that powersthe device, with the understanding that although the dipole antenna ispreferably straight, it may also be to some extent twisting ormeandering. The length of the antenna in turn determines the preferredfrequency of received electromagnetic energy. For example, for an 8.2 cmantenna, the preferred frequency may be 868 MHz, and for a 4 cm antenna,the preferred frequency may be 1.775 GHz. For use of frequencies in theunlicensed ISM/SRD bands of 2.400 to 2.4835 GHz, the preferred antennalength may be 2.85 to 2.95 cm. Thus, as the number of electrodes housedby the device decreases, the antenna length will generally decrease,resulting in the need to use higher frequency electromagnetic waves topower the device.

FIG. 2C illustrates an exemplary electrode assembly 340 on the device300 according to a preferred embodiment of the present invention. Thedevice contains two electrodes in a cylindrical-style stimulator. Asshown, electrode assembly 340 includes an active electrode 502 and areturn electrode 504 coupled to the pulse generating circuits of thedevice 300. Active and return electrodes 502 and 504, respectively, arespaced a suitable distance to allow for the formation of anelectromagnetic field around electrode assembly 340 for modulation ofnerve(s) at the target region (not shown). In this embodiment,electrodes 502 and 504 are spaced from each other with insulatingmaterial 205 by about 5-50 mm, preferably between about 10-20 mm. Asshown, the electrodes are exposed along only part of the diameter of thecylinder, so as to be able to direct the formed electromagnetic fieldpulses in a particular direction, namely, towards the nerve that theyare intended to stimulate.

Although there are a number of sizes and shapes that would suffice toimplement electrodes 502 and 504, by way of example, electrodes may bebetween about 1.0-1.5 mm long (such as 1.2 mm), may have an outsidediameter of between about 2.6-2.85 mm (such as 2.7 mm), and may have aninside diameter of between about 2.5-2.75 mm (such as 2.7 mm). Asuitable electrode may be formed from Pt-IR (90%/10%), although othermaterials or combinations or materials may be used, such as platinum,tungsten, gold, copper, palladium, silver.

Those skilled in the art will also recognize that a variety of differentshapes and sizes of electrodes may be used. By way of example only,electrode shapes according to various aspects of the present inventioncan include ball shapes, twizzle shapes, spring shapes, twisted metalshapes, annular shapes, solid tube shapes, flat shapes or the like.Alternatively, the electrode(s) may comprise a plurality of filaments,rigid or flexible brush electrode(s), coiled electrode(s) or the like.Alternatively, the electrode may be formed by the use of formed wire(e.g., by drawing round wire through a shaping die) to form electrodeswith a variety of cross-sectional shapes, such as square, rectangular, Lor V shaped, or the like.

The device shown in FIG. 2C differs from the devices shown in FIGS. 2Aand 2B in that it contains a connecting piece 210 that is interposedbetween the part of the device 300 containing the electrodes 340 and thetubing 201. The purpose of the connecting piece 210 is to make it easyto disconnect the tubing from the stimulator device 300 once the deviceis finally implanted. The connecting piece 210 shown in FIG. 2D containsa male part 211 and a female part 212 that interconnect with one anotherwhen the tubing 201 is being used to position the device 300. The malepart is permanently connected to the tubing, and the female part isconnected permanently to the device 300. The parts are held togetherwith thread or wire 213 that is threaded through aligned holes in theinsert 215 of the male part 211 and walls of the groove 216 of thefemale part 212. As shown in FIG. 2E, when the thread is pulled out, theinterconnecting male part 211 disconnects from the female part 212 whenthe tubing 201 is pulled.

An alternate connecting piece 210 is shown in FIG. 2F. In that case, amale part 218 and a female part 219 interconnect with one another whenthe tubing 201 is being used to position the device 300. The male partis permanently connected to the tubing 201, and the female part isconnected permanently to the device 300. The pieces are mated through aninsert 215 in the male part 218 that is situated in a groove 216 of thefemale part 219. In this case, the pieces are held togethermagnetically, rather than by a thread through aligned holes. As shown,the male part 218 is an electromagnet that is powered when the tubing201 is being used to position the stimulator 300. The electromagnetcomprises a coil wound around a core of ferromagnetic material such assoft iron. The magnetic field that the electromagnet produces holds thefemale part 219 to the male part 218, because the female part is eithera permanent magnet or is made of soft-magnetic material, i.e., itbecomes magnetic in the presence of the magnetic field produced by theelectromagnet (e.g., a piece of iron). When current through windings ofthe electromagnet is turned off, the male and female pieces willseparate when the tubing 201 is pulled.

An advantage of using the connecting piece 210 shown in FIG. 2F is thatit allows the device 300 to be re-positioned magnetically after thetubing 201 and its attached male part 218 have been removed. This isbecause a magnetic field applied externally to the patient may be usedto manipulate the location and orientation of the female part 219 inFIG. 2F (and therefore the stimulator 300 to which the female part 219is permanently attached), whether the female part is a permanent magnetor is made of soft-magnetic material [GILLIES, G. T., Ritter, R. C.,Broaddus, W. C., Grady, M. S., Howard, M. A., and McNeil, R. G. Magneticmanipulation instrumentation for medical physics research. Review ofScientific Instruments 65(3, 1994):533-562; Jake J. ABBOTT, OlgacErgeneman, Michael P. Kummer, Ann M. Hirt, and Bradley J.Nelson.Modeling magnetic torque and force for controlled manipulation ofsoft-magnetic bodies. IEEE Transactions on Robotics 23(6,2007)1247-1252].

The requirements for device re-positioning would be based upon images ofthe device 300 in its originally implanted site and orientation, ascompared with images of the device in its present, presumably non-ideal,site or orientation. Such imaging may involve different potentialimaging modalities, such as fluoroscopy or MRI. The preferred imagingmethods involve ultrasound, as described below in connection with theuse of ultrasound imaging to implant the stimulator device. In order toexplain the invention's methods for imaging and implanting the device300 into the neck of the patient, it is first necessary to summarize therelevant anatomy of the neck, as follows.

FIG. 3A illustrates some of the major structures of the neck. As shown,the common carotid artery 100 extends from the base of the skull 102through the neck 104 to the first rib and sternum (not shown). Carotidartery 100 includes an external carotid artery 106 and an internalcarotid artery 108 and is protected by fibrous connective tissue calledthe carotid sheath. The carotid sheath is located at the lateralboundary of the retopharyngeal space at the level of the oropharynx oneach side of the neck 104 and deep to the sternocleidomastoid muscle.The three major structures within the carotid sheath are the commoncarotid artery 100, the internal jugular vein 110 and the vagus nerve(not shown). The carotid artery lies medial to the internal jugular veinand in most patients, the vagus nerve is situated posteriorly betweenthe two vessels.

FIG. 3A also illustrates the approximate locations of the cervicalvertebrae C1 through C7. The thyroid cartilage, the largest of thecartilages that make up the cartilage structure in and around thetrachea that contains the larynx, lies at the vertebral levels of C4 andC5. The laryngeal prominence 111 (Adam's apple) in the middle of theneck is formed by the thyroid cartilage at approximately vertebral levelC4. Inferiorly, the ring of the cricoid cartilage (the only completering of cartilage around the trachea) may be palpated at vertebral levelC6. A flexion-extension palpation method may be used to identifyvertebral level C7 [Seokyung SHIN, Duck-Mi Yoon, and Kyung Bong Yoon.Identification of the correct cervical level by palpation of spinousprocesses. Anesth Analg 112(2011):1232-1235].

As indicated above, the vagus nerve is situated within the carotidsheath, near the carotid artery and the interior jugular vein. The leftvagus nerve is sometimes selected for stimulation because stimulation ofthe right vagus nerve may produce undesired effects on the heart, butdepending on the application, the right vagus nerve or both right andleft vagus nerves may be stimulated instead. Typically, the location ofthe carotid sheath or interior jugular vein in a patient (and thereforethe location of the vagus nerve) will be ascertained preliminarily byfeel and eventually by ultrasound imaging. Proceeding from the skin andfat of the neck to the vagus nerve, the shortest line may passsuccessively through the platysma muscle 82, the sternocleidomastoidmuscle 65, and the carotid sheath (see FIG. 3B and 3C). If such directaccess to the vagus nerve is desired, it may be attempted at about thelevel of cervical vertebra C5 to C6, although direct access to the vagusnerve through the sternocleidomastoid muscle 65 might also be attemptedanywhere between the middle of vertebra C4 and the middle of vertebraC7. Access at more cephalad vertebrae levels is ordinarily avoidedbecause the carotid sheath there also contains nerve branches of theansa cervicalis, which is part of the cervical plexus located from theC1 to C4 cervical segment in the neck. A less direct route to thecarotid sheath (and vagus nerve) may be along a line that passes justoutside the edge of the sternocleidomastoid muscle 65 at the boundary ofthe posterior or anterior triangles (FIG. 3C).

FIG. 4A provides a more detailed cross-sectional view of the patient'sneck, which may be viewed using an ultrasound transducer/probe placed atapproximately the indicated location at the level of vertebra C6. Thepreferred ultrasound transducer/probe style is shown to be the“hockey-stick” style, so-called because of its compact and unobtrusiveshape, which is commercially available from most ultrasound machinemanufacturers. By way of example, the Hitachi Aloka UST-536 19 mm HockeyStick style Transducer for superficial viewing has a frequency range of6-13 MHz, a scan angle of 90 degrees, and a scan width of 19 mm (HitachiAloka Medical America, 10 Fairfield Boulevard, Wallingford Conn. 06492).

The vagus nerve 60 is identified in FIG. 4A, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Structures that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65 (see also FIG. 6, in whichthe sternocleidomastoid muscle protrudes when the patient turns hishead). Additional organs in the vicinity of the vagus nerve include thetrachea 66, thyroid gland 67, esophagus 68, scalenus anterior muscle 69,scalenus medius muscle 70, levator scapulae muscle 71, splenius collimuscle 72, semispinalis capitis muscle 73, semispinalis colli muscle 74,longus colli muscle and longus capitis muscle 75. The sixth cervicalvertebra 76 is shown with bony structure indicated by hatching marks.Additional structures shown in the figure are the phrenic nerve 77,sympathetic ganglion 78, brachial plexus 79, vertebral artery and vein80, prevertebral fascia 81, platysma muscle 82, omohyoid muscle 83,anterior jugular vein 84, sternohyoid muscle 85, and sternothyroidmuscle 86.

The anatomy shown in FIG. 4A may be regarded as typical, but it shouldbe understood that the implantation of the stimulator device must takeinto account the anatomical variability that is observed from individualto individual. In approximately 5 percent of individuals, the vagusnerve has an unusual anatomical course that is possibly associated withabnormal thyroid gland anatomy. Also, the vagus nerve of approximately25% of individuals has an atypical position within the carotid sheath[GIBSON A. Bilateral abnormal relationship of the vagus nerve in itscervical portion. J Anat Physiol 49(1915):389-392; TUBBS R S, Loukas M,Shoja M M, Blevins D, Humphrey R, Chua G D, Kelly D R, Oakes W J. Anunreported variation of the cervical vagus nerve: anatomical andhistological observations. Folia Morphol (Warsz) 66(2, 2007):155-157;PARK J K, Jeong S Y, Lee J H, Lim G C, Chang J W. Variations in thecourse of the cervical vagus nerve on thyroid ultrasonography. AJNR Am JNeuroradiol 32(7, 2011):1178-1181; DIONIGI G, Chiang F Y, Rausei S, Wu CW, Boni L, Lee K W, Rovera F, Cantone G, Bacuzzi A. Surgical anatomy andneurophysiology of the vagus nerve (VN) for standardised intraoperativeneuromonitoring (IONM) of the inferior laryngeal nerve (ILN) duringthyroidectomy. Langenbecks Arch Surg 395(7, 2010):893-899; BROWN H,Hidden G, Ledroux M, Poitevan L. Anatomy and blood supply of the lowerfour cranial and cervical nerves: relevance to surgical neck dissection.Proc Soc Exp Biol Med 223(4, 2000):352-361].

Anatomical variation within the carotid sheath, as reported by DIONIGIet al, is illustrated in FIG. 4B, along with the approximate percentageof individuals having that anatomy. In approximately 73% of individuals,the location of the vagus nerve is as shown in FIG. 4A, in which thenerve is in a posterior location within the carotid sheath between thecommon carotid artery and internal jugular vein (Type 1). Inapproximately 15% of individuals, the nerve is in a posterior locationbut is closely associated with the common carotid artery (Type 2). Inapproximately 8% of individuals, the nerve is in a posterior locationbut is closely associated with the internal jugular vein (Type 3). Andin approximately 4% of individuals, the nerve is in an anterior locationwithin the carotid sheath between the common carotid artery and internaljugular vein (Type 4). The apparent reason for the existence of suchanatomical variability is that the fetal vagus nerve migrates within thecarotid sheath, and this migration may be incomplete or unusual in someindividuals [MIYAKE N, Hayashi S, Kawase T, Cho B H, Murakami G,Fujimiya M, Kitano H. Fetal anatomy of the human carotid sheath andstructures in and around it. Anat Rec (Hoboken) 293(3, 2010):438-445].

The conventional method for locating a cervical vagus nerve involves thepalpation of anatomical landmarks such as muscles, bones, cartilage andblood vessels by the treatment provider. This method is inexact becauseof individual variations in patient anatomy, which should be consideredin devising the anatomical path along which implantation of thestimulator in the vicinity of the vagus nerve is performed. Preferably,the location of a vagus nerve is determined by imaging with anultrasound probe as shown in FIG. 4A [KNAPPERTZ V A, Tegeler C H, HardinS J, McKinney W M. Vagus nerve imaging with ultrasound: anatomic and invivo validation. Otolaryngol Head Neck Surg 118(1, 1998):82-85;GIOVAGNORIO F and Martinoli C. Sonography of the cervical vagus nerve:normal appearance and abnormal findings. AJR Am J Roentgenol 176(3,2001):745-749]. On transverse scans, the vagus nerve has a honeycombappearance with 2 to 4 hypoechoic rounded fascicles surrounded by ahyperechoic epineurium. In addition to an unusual anatomical course ofthe vagus nerve, the ultrasound imaging may also reveal potentialproblems such as inflammation of the nerve that may contraindicate theuse of vagus nerve stimulation [Einar P V WILDER-SMITH. NerveUltrasound: Ready for clinical practice? Neurology Asia 17(1,2012):1-4].

To the extent that there is variation in the distance between the skinand vagus nerve as a function of position up and down the neck, thestimulator is preferably implanted in such a way that the distance isminimized. Accordingly, in a preferred embodiment of the invention, thevagus nerve is imaged as shown in FIG. 4A, continuously from thevertebra levels C4 to C7, so as to construct a three-dimensional imageof the carotid sheath within the neck, along with surrounding tissue.This is accomplished by attaching the ultrasound transducer to acomputer-controlled positioning device that moves the transducer downthe neck, storing images of the ultrasound images along the way. Thiscomputer-controlled device will also be used for the robotic insertionof a needle into the neck, as described below in connection with FIG. 9.

The ultrasound imaging will also be used to identify and locatestructures lying near the vagus nerve, or along the implantation path,that may be either potentially damaged during implantation of theelectrode or unintentionally electrically stimulated along with thevagus nerve [Barys IHNATSENKA and André P Boezaart. Applied sonoanatomyof the posterior triangle of the neck. Int J Shoulder Surg 4(3, 2010):63-74]. These include blood vessels, cervical sympathetic ganglia, andthe phrenic nerve. Large blood vessels such as the common carotid arteryor internal jugular vein are most easily identified by using color flowDoppler ultrasound imaging. We note too that the internal jugular veinis collapsible with slight pressure of the ultrasound probe. Smallervessels that may be damaged by the implantation procedure may also beidentified with the aid of gas-filled microbubbles as a contrast agent,as now described.

The human vagus nerve is supplied by a distinct vagal artery and veinthat lie on the anterior aspect of the nerve [FERNANDO D A, Lord R S.The blood supply of vagus nerve in the human: its implication in carotidendarterectomy, thyroidectomy and carotid arch aneurectomy. Ann Anat176(4, 1994):333-337]. KNAPPERTZ et al (cited above) were unable todelineate the vagal artery with color flow Doppler ultrasound imaging.However, conventional Doppler-based imaging techniques are unable todetect low velocity blood flow in smaller vessels, the chief difficultybeing that blood is a weak reflector of ultrasound. One method toovercome this difficulty is to inject brighter ultrasound reflectorsthan blood into the vascular system. Gas filled microbubbles are onesuch reflector or contrast agent [Matthew BRUCE, Mike Averkiou, and JeffPowers. Ultrasound contrast in general imaging research. (2007). PhilipsMedical Systems, Global Information Center, P.O. Box 1286, 5602 B GEindhoven, The Netherlands, pp. 1-19].

Note that this microbubble method may be useful not only for identifyingthe course and density of vagus nerve blood vessels, but also fortesting the operation of the electrical stimulator and determiningwhether the vagus nerve has been damaged, for the following reason. Whenthe vagus nerve is electrically stimulated, its metabolic needsincrease, such that there is reflex-increased blood flow within thevagal artery and its associated arterioles. Thus, one test for whetherthe vagus nerve is being stimulated is to measure blood flow in thevagal artery and compare it with the flow when the vagus nerve is notbeing stimulated. Therefore, according to the present invention, onemethod for demonstrating stimulation of a vagus nerve is to measure achange in vagal artery blood flow, preferably using ultrasound contrastagents.

In some species such as the pig, the cervical sympathetic chain lieswithin the carotid sheath alongside the vagus nerve [DING P, Tufano R P,Campbell-Malone R, Feng W, Kim S J, German R Z. Horner syndrome aftercarotid sheath surgery in a pig: anatomic study of cervical sympatheticchain. Comp Med 61(5, 2011):453-456]. In humans, the cervicalsympathetic chain, which may be imaged using an ultrasound transducer,lies outside the carotid sheath. Nevertheless, in some individuals, itmay lie quite close to the sheath [Philip W H PENG and Samer Narouze.Sonoanatomy of the Cervical Sympathetic Chain. Chapter 3 (pp 31-44) In:Samer Nabil Narouze.Ultrasound Guidance for Interventional PainManagement of Cervical Pain Syndromes An anatomical and clinical study.Dissertation at the Universiteit Maastricht. Minderbroedersberg 4-6,6211 L K Maastricht, The Netherlands (2012)]. Therefore, in suchindividuals, care must be taken to avoid damaging or electricallystimulating the sympathetic chain, such as the middle cervical ganglion(78 in FIG. 4A). Otherwise, the patient may develop Horner syndrome,with symptoms affecting the eye and face.

The phrenic nerve in humans may also lie close to a vagus nerve (77 inFIG. 4A), although the distance may again vary from individual toindividual. The likelihood of electrical co-stimulation of the vagus andphrenic nerves is sufficiently great that it has been the subject of apatent application that seeks to minimize the co-stimulation effects.Thus, in patent application JP2008/081479A, entitled Vagus nervestimulation system, to YOSHIHOTO, a system is described for keeping theheart rate within safe limits. When the heart rate is too high, thatsystem stimulates a patient's vagus nerve, and when the heart rate istoo low, that system tries to achieve stabilization of the heart rate bystimulating the heart itself, rather than use different parameters tostimulate the vagus nerve. In that disclosure, vagal stimulation uses anelectrode, which is described as either a surface electrode applied tothe body surface or an electrode introduced to the vicinity of the vagusnerve. It discloses electrical stimulation during particular phases ofthe respiratory cycle, for the following reason. Because the vagus nerveis near the phrenic nerve, Yoshihoto indicates that the phrenic nervewill sometimes be electrically stimulated along with the vagus nerve.The phrenic nerve controls muscular movement of the diaphragm, soconsequently, stimulation of the phrenic nerve causes the patient tohiccup or experience irregular movement of the diaphragm, or otherwiseexperience discomfort. To minimize the effects of irregular diaphragmmovement, Yoshihoto's system is designed to stimulate the phrenic nerve(and possibly co-stimulate the vagus nerve) only during the inspirationphase of the respiratory cycle and not during expiration. Furthermore,the system is designed to gradually increase and then decrease themagnitude of the electrical stimulation during inspiration (notablyamplitude and stimulus rate) so as to make stimulation of the phrenicnerve and diaphragm gradual.

If the vagus and phrenic nerves in an individual are sufficiently closeto one another to be electrically co-stimulated, there is also thepossibility that the phrenic nerve may be damaged during theimplantation of a vagus nerve stimulator. However, such damage may beavoided if the location of the phrenic nerve is first imaged using theultrasound probe. According to KESSLER et al, the location of thephrenic nerves is a function of the vertebral level. They found that thephrenic nerve and brachial plexus (79 in FIG. 4A) are within 2 mm ofeach other at the cricoid cartilage level, with additional 3 mmseparation for every cm more caudal in the neck. However, this too mayvary from individual to individual [KESSLER J, Schafhalter-Zoppoth I,Gray A T. An ultrasound study of the phrenic nerve in the posteriorcervical triangle: implications for the interscalene brachial plexusblock. Reg Anesth Pain Med 33(6, 2008):545-550]. Other nerves that couldbe potentially damaged in some individuals, because of their proximityto the carotid sheath, and because they are possibly in the path ofimplantation, are the spinal accessory nerve and superior cardiac nerve[Ong Cheng KANG and Chong Vincent Fook Hin. The glossopharyngeal, vagusand spinal accessory nerves. European Journal of Radiology 74 (2010)359-367].

One preferably implants the vagus nerve stimulator in such a way as tobe as distant as possible from other nerves, also orienting thestimulator's electrodes (e.g., 502 and 504 in FIG. 2C) towards the vagusnerve and away from other nerves. Nevertheless, depending on theindividual patient, some co-stimulation of other nerves may beunavoidable. Even within a vagus nerve, one prefers to stimulateparticular fiber types and avoid stimulation of other fiber types, andthis selectivity cannot be achieved simply by adjustment of the positionof the stimulator. In the case of vagal fiber selectivity, preferentialnerve fiber stimulation is accomplished by selection of the stimuluswaveform, and the same type of waveform-selective stimulation may beused to preferentially activate only the vagus nerve, as now described.Selectivity that is achieved through physical placement of thestimulator will be described later, in connection with the methods thatare used to implant the stimulator.

A waveform may be designed to selectively stimulate only one of twonerves whether the nerves lie close to one another or not, obviating theneed to focus the stimulating signal onto only one of the nerves [GRILLW and Mortimer J T. Stimulus waveforms for selective neural stimulation.IEEE Eng. Med. Biol. 14 (1995): 375-385]. Waveform selection methodscomplement others that are used to achieve selective nerve stimulation,such as the use of local anesthetic, application of pressure, inducementof ischemia, cooling, use of ultrasound, graded increases in stimulusintensity, exploiting the absolute refractory period of axons, and theapplication of stimulus blocks [John E. SWETT and Charles M. Bourassa.Electrical stimulation of peripheral nerve. In: Electrical StimulationResearch Techniques, Michael M. Patterson and Raymond P. Kesner, eds.Academic Press. (New York, 1981) pp. 243-295]. Parameters for the nervestimulation include power level, frequency and train duration (or pulsenumber). The stimulation characteristics of each pulse, such as depth ofpenetration, strength and selectivity, depend on the rise time and peakelectrical energy transferred to the electrodes, as well as the spatialdistribution of the electric field that is produced by the electrodes.The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes, as well as by theanatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmur

o, Przemystaw P

onecki, Jacek Starzyński, Stanis

aw Wincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 5A illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are produced within the patient by the electrodes.As shown, a suitable electrical voltage/current profile 400 for theblocking and/or modulating impulse 410 to the portion or portions of anerve may be achieved using pulse generator 310. In a preferredembodiment, the pulse generator 310 may be implemented using a powersource 320 and a control unit 330 having, for instance, a processor, aclock, a memory, etc., to produce a pulse train 420 to the electrodes340 that deliver the stimulating, blocking and/or modulating impulse 410to the nerve. The parameters of the modulation signal 400, such as thefrequency, amplitude, duty cycle, pulse width, pulse shape, etc., arepreferably programmable. An external communication device may modify thepulse generator programming to improve treatment (380 in FIG. 1A).

In addition, techniques according to the device disclosed in patentpublication No. US2005/0216062 may be employed. That patent publicationdiscloses a multifunctional electrical stimulation (ES) system adaptedto yield output signals for effecting electromagnetic or other forms ofelectrical stimulation for a broad spectrum of different biological andbiomedical applications, which produce an electric field pulse. Thesystem includes an ES signal stage having a selector coupled to aplurality of different signal generators, each producing a signal havinga distinct shape, such as a sine wave, a square or a saw-tooth wave, orsimple or complex pulse, the parameters of which are adjustable inregard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the tissue being treated, as well as the outputs ofvarious sensors which sense prevailing conditions prevailing in thistissue, whereby the user of the system can manually adjust the signal,or have it automatically adjusted by feedback, to provide an electricalstimulation signal of whatever type the user wishes, who can thenobserve the effect of this signal on a tissue being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, square, triangular or trapezoidal waves are preferredwaveforms for stimulation. The electrical impulse will typically have afrequency of between about 1-500 Hz, preferably about 1 to 50 Hz, andmore preferably about 10-35 Hz. In an exemplary embodiment, thefrequency for the impulse received by the nerve is about 25 Hz. Thepreferred fixed voltage received by the nerve is between about 1-20 Vand will typically vary depending on the size and type of electrode andthe distance between the electrode and the nerve. In certain embodimentswhere the nerve is directly attached to the nerve (or implanted adjacentto the nerve), the fixed voltage is preferably about 1 to 4 volts, morepreferably about 2 volts. In other embodiments, wherein the electrodeis, for example, injected into the patient and implanted outside of thesheath, the voltage is preferably between about 7-15 volts and morepreferably about 10 V. In embodiments wherein the current is fixed orheld constant, the preferred fixed current is about 0.5 mA to about 20mA. Similar to voltage, the fixed current will vary depending on thesize and type of electrode and its distance from the nerve. In thoseembodiments where the electrode is adjacent to, or on, the nerve, thecurrent is preferably about 0.5 to 5 mA and more preferably about 3.5mA. In those embodiments, where the electrode is spaced from the nerve(just as an injectable electrode outside of the sheath), the current ispreferably about 7-15 mA and more preferably about 10 mA. The modulationsignal may have a pulse width selected to influence the therapeuticresult, such as about 1 microsecond to about 1000 microseconds,preferably about 200 microseconds. For example, the electric fieldinduced or produced by the device within tissue in the vicinity of anerve may be about 5 to 600 V/m, preferably less than 100 V/m, and evenmore preferably less than 30 V/m. The gradient of the electric field maybe greater than 2 V/m/mm. More generally, the stimulation deviceproduces an electric field in the vicinity of the nerve that issufficient to cause the nerve to depolarize and reach a threshold foraction potential propagation, which is approximately 8 V/m at 1000 Hz.

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inpatent number U.S. Pat. No. 6,234,953, entitled Electrotherapy deviceusing low frequency magnetic pulses, to THOMAS et al. and applicationnumber US20090299435, now U.S. Pat. No. 7,983,762, entitled Systems andmethods for enhancing or affecting neural stimulation efficiency and/orefficacy, to GLINER et al. One may also vary stimulation parametersiteratively, in search of an optimal setting [U.S. Pat. No. 7,869,885,entitled Threshold optimization for tissue stimulation therapy, toBEGNAUD et al]. However, some stimulation waveforms, such as thosedescribed herein, are discovered by trial and error, and thendeliberately improved upon.

In other embodiments, bursts of sinusoidal pulses are used as astimulation waveform, as shown in FIG. 5B and 5C. As seen there,individual sinusoidal pulses have a period of □ and a burst consists ofN such pulses. This is followed by a period with no signal (theinter-burst period). The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period □ may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation (a much smaller value of T is shown inFIG. 5C to make the bursts discernable). When these exemplary values areused for T and □ the waveform contains significant Fourier components athigher frequencies (1/200 microseconds=5000/sec), as compared with thosecontained in nerve stimulation waveforms, as currently practiced.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters □ N, and T may also be dissimilar from the values exemplifiedabove [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, and R. C. Lehman.Electrical stimulation of the quadriceps femoris in an elite weightlifter: a single subject experiment. Int J Sports Med 10(1989):187-191;Alex R WARD, Nataliya Shkuratova. Russian Electrical Stimulation: TheEarly Experiments. Physical Therapy 82 (10, 2002): 1019-1030; YochevedLAUFER and Michal Elboim. Effect of Burst Frequency and Duration ofKilohertz-Frequency Alternating Currents and of Low-Frequency PulsedCurrents on Strength of Contraction, Muscle Fatigue, and PerceivedDiscomfort. Physical Therapy 88 (10, 2008):1167-1176; Alex R WARD.Electrical Stimulation Using Kilohertz-Frequency Alternating Current.Physical Therapy 89 (2, 2009):181-190; J. PETROFSKY, M. Laymon, M.Prowse, S. Gunda, and J. Batt. The transfer of current through skin andmuscle during electrical stimulation with sine, square, Russian andinterferential waveforms. Journal of Medical Engineering and Technology33 (2, 2009): 170-181; U.S. Pat. No. 4,177,819, entitled Musclestimulating apparatus, to KOFSKY et al]. Burst stimulation has also beendisclosed in connection with implantable pulse generators, but whereinthe bursting is characteristic of the neuronal firing pattern itself[U.S. Pat. No. 7,734,340 to DE RIDDER, entitled Stimulation design forneuromodulation; application US20110184486, now U.S. Pat. No. 8,364,273,to DE RIDDER, entitled Combination of tonic and burst stimulations totreat neurological disorders]. By way of example, the electric fieldshown in FIGS. 5B and 5C may have an E_(max) value of 17 V/m, which issufficient to stimulate the nerve but is significantly lower than thethreshold needed to stimulate surrounding muscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, now U.S. Pat.No. 8,355,792, entitled Selective high frequency spinal cord modulationfor inhibiting pain with reduced side effects and associated systems andmethods, to ALATARIS et al.; Adrian A L KAISY, Iris Smet, andJean-Pierre Van Buyten. Analgeia of axial low back pain with novelspinal neuromodulation. Poster presentation #202 at the 2011 meeting ofThe American Academy of Pain Medicine, held in National Harbor, Md.,Mar. 24-27, 2011].

Those methods involve high-frequency modulation in the range of fromabout 1.5 KHz to about 50 KHz, which is applied to the patient's spinalcord region. However, such methods are different from the presentinvention because, for example, they do not involve a bursting waveform,as in the present invention; they necessarily involve A-delta and Cnerve fibers and the pain that those fibers produce, whereas the presentinvention does not; they may involve a conduction block applied at thedorsal root level, whereas the present invention may stimulate actionpotentials without blocking of such action potentials; and/or theyinvolve an increased ability of high frequency modulation to penetratethrough the cerebral spinal fluid, which is not relevant to the presentinvention. In fact, a likely explanation for the reduced back pain thatis produced by their use of frequencies from 10 to 50 KHz is that theapplied electrical stimulus at those frequencies causes permanent damageto the pain-causing nerves, whereas the present invention involves onlyreversible effects [LEE R C, Zhang D, Hannig J. Biophysical injurymechanisms in electrical shock trauma. Annu Rev Biomed Eng2(2000):477-509].

However, the threshold for activation of fiber types also depends on theamplitude and/or duration of the stimulation, and for a givenstimulation frequency, the threshold increases as the fiber sizedecreases. The threshold for generating an action potential in nervefibers that are impaled with electrodes is traditionally described byLapicque or Weiss equations, which describe how together the width andamplitude of stimulus pulses determine the threshold, along withparameters that characterize the fiber (the chronaxy and rheobase). Fornerve fibers that are stimulated by electric fields that are appliedexternally to the fiber, as is the case here, characterizing thethreshold as a function of pulse amplitude and frequency is morecomplicated, which ordinarily involves the numerical solution of modeldifferential equations or a case-by-case experimental evaluation [DavidBOINAGROV, Jim Loudin and Daniel Palanker. Strength-DurationRelationship for Extracellular Neural Stimulation: Numerical andAnalytical Models. J Neurophysiol 104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 to100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS MS, Verma-Ahuja S, Naritoku DK, Espinosa JA.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110(2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the large A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282(1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

For acute treatments, the nerve stimulation may be administered for apredetermined duration, such as between about 5 minutes and about 1hour, or between about 5 minutes and about 24 hours. For othertreatments, the nerve stimulation may be administered as the needarises, or on an intermittent schedule over a period of days or weeks. Amore complete description of the protocols for administering the vagusnerve therapy for particular conditions is found in commonly assigned,co-pending applications that are listed in the section Cross Referenceto Related Applications of this application, which are incorporated byreference.

The implantation of conventional vagus nerve stimulators using spiralelectrodes is ordinarily performed in open neck surgery, with thepatient under general anesthesia[Arun Paul AMAR, Michael L. Levy,Charles Y. Liu and Michael L. J. Apuzzo. Chapter 50. Vagus nervestimulation. pp. 625-638, particularly 634-635. In: Elliot S. Krames, P.Hunber Peckham, Ali R. Rezai, eds. Neuromodulation. London: AcademicPress, 2009; KIRSE D J, Werle A H, Murphy J V, Eyen T P, Bruegger D E,Hornig G W, Torkelson R D. Vagus nerve stimulator implantation inchildren. Arch Otolaryngol Head Neck Surg 128(11, 2002):1263-1268]. Forimplantation of stimulator devices of the types illustrated in FIG. 2,however, the patient could be anesthetized only locally in the neck. Wenote that even the implantation of vagus nerve stimulators in opensurgery, as well as carotid endartectomy and thyroid surgery, which areneck surgeries that are considerably more invasive than what isdescribed here, are sometimes also performed using only localanesthesia. Those local anesthesia methods may also be used in thepresent invention [BERNARD E J, Passannante A N, Mann B, Lannon S,Vaughn B V. Insertion of vagal nerve stimulator using local and regionalanesthesia. Surg Neurol 57(2, 2002):94-98; J R SPARGO and D Thomas.Local anaesthesia for carotid endarterectomy. Continuing Education inAnaesthesia, Critical Care & Pain 4(2, 2004):62-65]. An advantage ofperforming the stimulator implantation with only local anesthesia isthat the patient can cooperate in monitoring the successful electricalstimulation by the device as described below, for example, by makingvocal sounds that are affected by electrical stimulation of a branch ofthe vagus nerve (the recurrent laryngeal nerve) or by damage to thevagus nerve.

Even so, it is understood that a vagus nerve stimulator such as the onesshown in FIG. 2, particularly the one in FIG. 2C after tube detachment,could also be implanted during open neck surgery, in lieu of, or inaddition to, the spiral electrode that is ordinarily implanted duringconventional vagus nerve stimulation implantation. One can considerimplanting more than one such stimulator about the vagus nerve. In oneconfiguration, two or more stimulators surround the nerve at aparticular vertebral level, each of which has its active and returnelectrodes facing the nerve. In another configuration, two or morestimulators may be implanted end-to-end, each with electrodes alsofacing the nerve, with the objective of increasing the nerve coverageover a greater distance along the nerve. In those cases, the stimulatorswould be constructed with permanently attached loops at their top andbottom, so that the loops could be used to suture the stimulators tosurrounding tissue or about the nerve itself. Alternatively, anchorageof the electrodes to the internal jugular vein, common carotid artery,and/or vagus nerve itself can make use of spring-like stimulatorattachments like those disclosed later in connection with FIGS. 7B and8B. Implantation of such an electrode in addition to the conventionalspiral electrode would be done in order to provide redundancy ofstimulation, for example, in the event that the conventional electrodesystem fails. This may be done during the open neck surgery as acontingency, but could also be done percutaneously subsequent to failureof the conventional stimulation system, in lieu of performing anotheropen neck surgery around scar tissue [ONEILL B R, Wilberger J E.Revision of vagal nerve stimulator electrodes through a posteriorcervical triangle approach: technical note. Neurosurgery 67(2 SupplOperative, 2010):457-460]. The conventional spiral electrode could alsobe used as support for the antenna of stimulators of the type shown inFIG. 2, or the spiral electrode itself can be adapted to serve as theantenna. These methods differ from those disclosed by TOCKMAN et al, forexample, in that the present methods make use of an antenna and do notmake use of a separate implanted pulse generator [Patent applicationUS20120022617, now U.S. Pat. No. 8,620,450, entitled Minimally invasivelead system for vagus nerve stimulation, to TOCKMAN et al].

FIGS. 6-12 illustrate implantation methods directed to the goal of beingable to apply an electrical impulse in or around the carotid sheath of apatient. Once the skin of the patient is cleaned and sterilized for theprocedure, the target area of the skin on the neck is anesthetized(e.g., with lidocaine or a similar local anesthesia). In a preferredembodiment, a finder needle may be used to first create a path to thetarget region in or around the carotid sheath. The finder needle ispreferably a small access needle having a size in the range of 18-26gauge, preferably around 22 gauge. Suitable finder needles for use inone or more embodiments of the present invention may be purchasedcommercially from Epimed (Epimed International, 13958 Diplomat Drive,Farmers Branch, Tex. 75234). Typically, the finder needle is insertedthrough the skin surface and advanced to approach or enter the carotidsheath, with its tip in the vicinity of the vagus nerve that is to beelectrically stimulated. If the finder needle has a lumen, the needlemay be aspirated to ensure that it has not penetrated a vessel such asthe jugular vein or carotid artery, and ultrasound may be used to verifythe exact placement of the finder needle.

An excitable tissue cell, such as a nerve fiber, is thought to besignificantly less sensitive to a transverse electric fieldperpendicular to the nerve than a longitudinal electric field parallelto the nerve. Applying a longitudinal field increases the effect of thisfield on the nerve fiber at given frequencies, amplitudes, pulsedurations and power levels, as compared with a transverse field. Thus,in these embodiments, the finder needle is preferably advanced toapproach the carotid sheath in parallel, assuming that the stimulatordevice is configured as shown in FIG. 2C. In other embodiments, thefinder needle may be advanced to positions transverse to the long axisof the carotid sheath, as shown in FIG. 1 in the following publication:MINER, J. R., Lewis, L. M., Mosnaim, G. S., Varon, J., Theodoro, D.Hoffman, T. J. Feasibility of percutaneous vagus nerve stimulation forthe treatment of acute asthma exacerbations. Acad Emerg Med 2012; 19:421-429.

Examples of parallel and transverse finder needle paths to the vagusnerve are illustrated in FIG. 6A. The anterior border 651, central ridge652, and posterior border 653 of the sternocleidomastoid muscle 65 areindicated in the figure, which may be readily identified from themuscle's bulge when the patient turns his neck far to the side, andwhich may be subsequently verified by ultrasound imaging. Transversepaths taken by the finder needle to the vagus nerve at the preferredvertebral level may be approached from the anterior border of the muscle661, from the muscle's central ridge 662, and from the posterior borderof the muscle 663. We note that the latter approach is sometimes used inopen neck surgery [ONEILL B R, Wilberger J E. Revision of vagal nervestimulator electrodes through a posterior cervical triangle approach:technical note. Neurosurgery 67(2 Suppl Operative, 2010):457-460]. Notetoo that the path taken by the finder needle will not necessarily beperfectly straight, as the needle finds a path of least resistance. Forexample, the transverse path along the posterior border 663 may progresswithin the prevertebral fascia (81 in FIG. 4A), which is not perfectlystraight. Parallel paths taken by the finder needle may be initiatednear vertebral level C6 or C7 and then be directed in the direction ofthe head to reach the vagus nerve atvertebral levels C4 to C6, and thesetoo may be approached from the anterior muscle border 671, from themuscle's central ridge 672, and from the posterior muscle border 673.Additional approaches are also possible, as used in biopsies of theneck, for example, approaches that go through a lobe of the thyroidgland [GUPTA S, Henningsen J A, Wallace M J, Madoff D C, Morello F A Jr,Ahrar K, Murthy R, Hicks M E. Percutaneous biopsy of head and necklesions with CT guidance: various approaches and relevant anatomic andtechnical considerations. Radiographics 27(2, 2007):371-390]. Suchalternate approaches would generally not be considered if the tubing 201of the device 300 were not detached and removed, as described inconnection with FIG. 2C

The preferred path that the finder needle takes in reaching the vagusnerve is based in part upon the anatomy of the patient, which ispreliminarily determined using ultrasound imaging. Thus, it is assumedthat the location of the vagus nerve within the carotid sheath is known(FIG. 4B), that the location of the phrenic nerve and sympatheticganglia near the vagus nerve have been determined, and that the locationand density of blood vessels, including small vessels, have beendetermined by color flow Doppler ultrasound in conjunction withmicrobubbles used as a contrast agent. A path may then be selected asbeing the most direct route to the vagus nerve, as well as thelikelihood that the other structures will not be damaged along the pathor stimulated by the implanted stimulator. For example, the decision maybe guided by the position of the vagus nerve 60 within the carotidsheath 61, in relation to the internal jugular vein 62 and commoncarotid artery 63, as illustrated in FIG. 6B. As illustrated there,different transverse paths might be selected. For the Type 1 position ofthe vagus nerve, the preferred path 662 may be to insert the finderneedle through the sternocleidomastoid muscle to a location between thecommon carotid artery and internal jugular vein until it reaches thevagus nerve. Alternatively, it may be decided that the safest path 661is an approach from the anterior border of the sternocleidomastoidmuscle to a position between the common carotid artery and internaljugular vein but outside the carotid sheath, or a similar approach fromthe posterior border of the muscle (not shown). In that regard, it isnoteworthy that stimulation of the vagus nerve can be accomplished froma location outside the carotid sheath [WU C W, Dionigi G, Chen H C, ChenH Y, Lee K W, Lu I C, Chang P Y, Hsiao P J, Ho K Y, Chiang F Y. Vagalnerve stimulation without dissecting the carotid sheath duringintraoperative neuromonitoring of the recurrent laryngeal nerve inthyroid surgery. Head Neck. 2012 Sep. 18. doi: 10.1002/hed.23154, pp.1-5].

For the Type 2 position of the vagus nerve, the preferred path 661 maybe to insert the finder needle from the anterior border of thesternocleidomastoid muscle. For a Type 3 position of the vagus nerve,the preferred path 663 may be to insert the finder needle from theposterior border of the sternocleidomastoid muscle. If the position ofthe vagus nerve were of Type 4 shown in FIG. 4B, the vagus nerve wouldalready be relatively near the surface of the skin. In that case, onecould consider implanting the stimulator along the path shown as 672 inFIG. 6A, to lie within or just outside the carotid sheath. However, onemight also simply insert the stimulator immediately under the skin withelectrodes directed towards the vagus nerve, without placing thestimulator deep to the sternocleidomastoid muscle. This presumes thatthe stimulator 300 can generate an electrical signal with sufficientamplitude to modulate the activity of the vagus nerve, considering thatas the distance of the vagus nerve from the skin is increased relativeto the distance from a point near the carotid sheath, the requiredamplitude would likewise increase.

If the simulator is like the one shown in FIG. 2C, the path 662 taken bythe finder needle for the Type 1 situation in FIG. 6B, between thecommon carotid artery and internal jugular vein, would not result in thestimulator's electrodes creating an electric field transverse to thevagus nerve. For such a path perpendicular to the vagus nerve, one wouldinstead use a stimulator 300 such as the one shown in FIG. 7 that canbend about a hinge 225 (or use another such flexible stimulator). Asdescribed below, after the finder needle has been positioned along apath such as 662 in FIG. 6B, a larger diameter cannula 601 may beintroduced adjacent to, or over the finder needle, and if the latter isthe case, the finder needle will be withdrawn from the lumen of thecannula 601. The cannula 601 will then accept the introduction of thestimulator 300 within its lumen, which in FIG. 7A is shown in itsstraight configuration. In addition to the hinge 225, parts of thestimulator 300 include active and return electrodes 502 and 504, aconnecting piece 210, and the lumen 204 of tubing 201. The cannula 601is shown as having a curved distal end, so that as the stimulator isadvanced to the end of the cannula, the stimulator is forced into thebent configuration shown in FIG. 7B. In that bent configuration, theelectrodes 502 and 504 can then create an electric field that isparallel to the vagus nerve. Thus, with such a stimulator, a parallelelectrode configuration can be produced, even if the finder needle isintroduced into the patient in a transverse direction.

FIG. 7 also shows optional components that may be used to attach thestimulator 300 to surrounding structures. In the straight configurationshown in FIG. 7A, the device contains ribbon springs 230 that are foldedagainst the tubing 201. After the stimulator assumes the final bentconfiguration shown in FIG. 7B, the cannula 601 will then be withdrawnso that the ribbon springs 230 are free to assume their unstressedconformations. To prevent them from relaxing to that conformation tooquickly as the cannula 601 is withdrawn, threads 234 may be used by theimplanter of the device to release the springs slowly. The springs willthen be used to hug adjacent tissue, such as the internal jugular veinor common carotid artery, thereby anchoring the stimulator in place.Surgical glue injected through the tubing 201, after detachmentconnecting piece 210 is separated (see FIG. 2), may also be used tofacilitate the anchoring, before the tubing 201 and threads 234 arecompletely withdrawn.

Such anchoring attachments may also be used with a stimulator that isintended to be implanted along a parallel path (e.g., paths 671, 672,and 673 in FIG. 6A). An example is shown in FIG. 8, in which a coiledspring 240 is initially wound around a stimulator 300 like the one shownin FIG. 2C. The stimulator 300 also comprises active and returnelectrodes 502 and 504, a lumen 204 of the tubing 201, and a connectingpiece 210. As with the electrode shown in FIG. 7, a cannula 601 willaccept the introduction of the stimulator 300 of FIG. 8 within itslumen, which in FIG. 8A is shown to be maintaining the coiled spring 240in its compact, coiled conformation. Once the stimulator 300 reaches itsultimate position near a vagus nerve of the patient, the cannula 601 iswithdrawn, and the stimulator may also be rotated about its long axis,so as to release the spring 240. The spring 240 is then free to hug anadjacent structure, such as the vagus nerve itself, thereby anchoringthe stimulator within the patient. It is understood that methods forconstructing springs of the type shown in FIGS. 7 and 8 are known in theart, wherein the spring may be deployed to exhibit predetermined shapeand mechanical properties, although they have not been described inconnection with the anchoring of percutaneous peripheral nervestimulators. Other such deployable attachments may be inflated [e.g.,U.S. Pat. No. 3,187,416, entitled Method for manufacturing spiralsprings, particularly for watch-making, to TUETEY et al; H PETROSKI.Engineering: Deployable Structures. American Scientist 92(2,2004)122-126].

To summarize the foregoing disclosure concerning the selection of theanatomical path to be taken by the finder needle—the path selectionincludes consideration of the length of the stimulator and the number ofits electrodes, whether the stimulator's electrodes should produce anelectric field that is intended to have particular directionality,whether deployable anchoring attachments will be used to secure thestimulator to particular surrounding tissue, as well as consideration ofthe electrical waveforms that may be used to preferentially stimulatethe vagus nerve and particular fibers within it, the most direct routeto the vagus nerve, the likelihood that the other structures will not bedamaged or eventually co-stimulated along the path, and the ease withwhich the finder needle may penetrate and actually follow the intendedpath. The selection will preferably be made after a thorough ultrasoundexamination of the patient's neck anatomy, even more preferably byconstructing a three-dimensional image that is available as data withina computer.

Introduction of the finder needle into the neck of the patient is themost risky aspect of the implantation procedure, because subsequentsteps of the procedure make use of the implantation path that hadalready been made by the finder needle. Thus, if damage is done to anystructure within the patient's neck by the implantation procedure, itwill most likely be done during the initial step of introducing thefinder needle. Consequently, the present invention contemplates the useof a robotic device that removes much of the risk associated with manualinsertion of the finder needle. Applicants are unaware of any previousattempt to perform percutaneous vagus nerve stimulator implantation witha robotic device. The only prior robotic surgery to implant a vagusnerve stimulator involved the use of the da Vinci surgical system duringopen neck surgery, under general anesthesia [LOBE T E, Wright S K, IrishM S. Novel uses of surgical robotics in head and neck surgery. JLaparoendosc Adv Surg Tech A. 15(6, 2005):647-652].

Components of the implantation robot 90 are shown in FIG. 9A, whichinserts a needle 91 into and through an entry point 92 on the patient'sskin. Actuators 93 and an X-Y-Z stage 94 that comprise the robot 90allow the robot to move and insert the needle in many possibledirections (shown by arrows in FIG. 9). Feedback control of thatmovement is possible because the robot also comprises sensors 96 formeasuring the force and position experienced by the needle, as well asan ultrasound imaging transducer/probe 95 that measures the progress ofthe needle 91 in relation to the anatomy of the patient's neck. Thetransducer is held firmly against the patient's skin by springs 97within an arm that is used to clamp the robot to a rigid supportingstand 98, wherein the variable angle of the clamping adds additionaldegrees of freedom to the positioning of the needle.

A block diagram showing the robot's control over needle placement isshown in FIG. 9B. Before the needle is advanced to the neck of thepatient, the robotic system preferably acquires a digitalthree-dimensional representation of the anatomy of the patient's neck,which is captured by the ultrasound transducer/probe 95 as the X-Y-Zstage 94 moves the transducer slowly down the patient's neck in adirection perpendicular to the two-dimensional ultrasound image. Thisimage acquisition may be performed in two or more passes, so as to takeinto account any movement of the patient's neck as a function of thephase of respiration (measured throughout the procedure by inductiveplethysmography, mercury in silastic strain gauges, impedancepneumography, etc.). The image acquisition may also be performed withthe neck turned to different positions, in order to be able to evaluatethe potential movement of a stimulator that is implanted in anypotential anatomical configuration or orientation, as the patient turnshis or her neck. From the images, the boundaries and identities oftissue within the images may be identified automatically or with manualediting. Using published or otherwise acquired data concerning thegenerally anisotropic mechanical properties of the various tissues, atentative three-dimensional mechanical map may be constructed from theimage data that can be used to estimate the force and mechanical momentthat the finder needle would experience as it progresses through thetissues. Such a map may also be used to predict the probability that theneedle would experience one or more deviant movements along the path,brought about, for example, by nonlinearities in the equations of motionfor the needle (see references below), uncertainty in the anatomy of thepatient, slippage, or potential movement of the neck that is due to thepatient's breathing or other factors. A set of preferred paths that theneedle could take within the patient is then calculated, based uponcriteria that were described above, and also by the likelihood that apath would also have a low probability of inadvertent needle placementor rotation. The potential paths would include a preferred time-courseof needle insertion, such as whether to pause advancement of the needleduring a particular phase of respiration, and how fast the needle shouldbe advanced at different locations along the path. A single target pathis then selected from among these potential paths.

The needle is then introduced into the patient's neck at the path'sentry point 92 and advanced into the neck, while force/moment, position,and ultrasound image data are acquired. Based upon those data, the robotcompensates for any discrepancies between the actual needle path andpreferred path, until the needle reaches its final destination withinthe patient's neck. As shown in FIG. 9B, the system automaticallyprocesses the ultrasound image data and sends results of the processing,along with needle force and position data to a data acquisition system.Data in that system are then read by a computer, which calculatesdiscrepancies between the actual needle path and the preferred path, andwhich then controls the actuators of the robot/manipulator to compensatefor any path deviations. Significant advantages of the robotic needleinsertion include the deliberate creation of paths that are notnecessarily straight lines, and the automatic identification orconfirmation of tissue layers as the needle is advanced, e.g., automaticrecognition of the fact that the carotid sheath has been entered andcrossed, by virtue of quantitative changes in the force required toadvance the needle there [Niki ABOLHASSANI, Rajni Patel, MehrdadMoallem. Needle insertion into soft tissue: A survey. MedicalEngineering & Physics 29 (2007) 413-431; Kyle B. REED, Ann Majewicz,Vinutha Kallem, Ron Alterovitz, Ken Goldberg, Noah J. Cowan, and AllisonM. Okamura. Robot-Assisted Needle Steering. IEEE Robot Autom Mag. 18(4,2011):35-46; Dedong G O A, Yong Lei, and Haojun Zheng. Needle steeringfor robot-assisted insertion into soft tissue: a survey. Chinese Journalof Mechanical Engineering 25(4, 2012):629-638; L. BARBE, B. Bayle, M. deMathelin, A. Gangi. Needle insertions modeling: Identifiability andlimitations. Biomedical Signal Processing and Control 2(3,2007):191-198; Niki ABOLHASSANI, Rajni V. Patel, Farzam Ayazi.Minimization of needle deflection in robot-assisted percutaneoustherapy. Int J Med Robotics Comput Assist Surg 3(2007):140-148; J HONG,T Dohi, M Hashizume, K Konishiand N Hata. An ultrasound-drivenneedle-insertion robot for percutaneous cholecystostomy. Phys. Med.Biol. 49(2004):441-455]. We note that the robot shown in FIG. 9 has amore compact and application-specific design than those used for generichead and neck surgery [OLIVEIRA C M, Nguyen H T, Ferraz A R, Watters K,Rosman B, Rahbar R. Robotic surgery in otolaryngology and head and necksurgery: a review. Minim Invasive Surg. 2012:286563, pp. 1-11]. We notetoo that the robotic device with ultrasound imaging capability alsodiffers from previous combined ultrasound/stimulation instruments, whichuse at least one surface electrode to stimulate a nerve and that do notuse robotics in the process of inserting an internal electrode to itsstimulation site [U.S. Pat. No. 7,789,833, entitled Integrated nervestimulator and ultrasound imaging device, to URBANO et al].

Once the finder needle is in place, a small incision may be made next tothe site at which the finder needle enters the patient's skin, e.g. witha scalpel, to provide access for insertion of a tubular introducer,through which the stimulator device will later be implanted in thepatient. The finder needle may be left in place and the introducer maybe advanced adjacent to it; or the introducer may be inserted over thefinder needle, such that the finder needle initially occupies a lumenwithin the introducer. In the latter case, the finder needle may bewithdrawn once the introducer occupies the path that had been created bythe finder needle. FIG. 10 illustrates an exemplary introducer 600according to one embodiment of the present invention. As shown,introducer 600 includes a needle assembly 602 and a sheath or cannula601. In this embodiment, needle assembly 602 is a syringe having aflexible hypodermic needle 603 coupled to a piston pump 604 with aplunger 606 that fits within a cylindrical hollow tube 608. If theneedle 603 and cannula 601 are inserted over the finder needle, then thepiston pump 604 will be attached to the needle 603 after the finderneedle is withdrawn, e.g., using a Luer-lock style fitting. As is wellknown in the art, plunger 606 can be pulled and pushed along the insideof tube 608 to take in and expel liquids or gases through an orifice(not shown) at the open end of tube 608. Cannula 601 includes a base 612and a hollow tube 610 sized to receive hypodermic needle 603 andstimulator device 300 (as discussed below). Although the specificcannula used is not of criticality to the invention, suitable cannulascan be purchased commercially from Epimed (Epimed International, 13958Diplomat Drive, Farmers Branch, Tex. 75234), In an alternativenon-preferred embodiment, an introducer 600 could be directly insertedinto patient without the use of a separate finder needle, or the needle603 could play the role of the finder needle, with the cannula 601subsequently inserted over it.

As shown in FIG. 10, tube 610 of introducer 600 is driven through thepercutaneous penetration 620 in the neck 622 of a patient and advancedalong the same entry path as the finder needle until it reaches thedesired depth of placement at the target region, in or around thecarotid sheath. The physician may also aspirate needle 603 to ensurethat it has not penetrated into a venous or arterial structure. Needleassembly 602 is then removed from cannula 601 by pressing against base612 while needle assembly 602 is withdrawn.

At this point, a lead blank may be inserted into the cannula 601 andadvanced to the target region. A lead blank is an instrument that hasthe approximate size and shape of the stimulator that will eventually beintroduced into the lumen, but that does not contain the stimulator'selectrodes. The lead blank is preferably blunt and coated with amaterial such as Teflon. The purpose of inserting the lead blank intothe cannula is to create a sufficiently large and open path, into whichthe stimulator can eventually be placed. Thus, the present method doesnot necessarily use traditional dissection prior to implanting of thestimulator. Instead, use of the lead blank is intended to clear out anyobstacles in connective tissue that are encountered, for example, inmaking sure that a hinged stimulator (FIG. 7) has enough room to turn.The alternative would be to actually attempt an endoscopic dissection[U.S. Pat. No. 7,819,883, entitled Method and apparatus for endoscopicaccess to the vagus nerve, to WESTLUND et al.].

Referring now to FIG. 11, stimulator 300 with tubing 201 that later maybe detached at the connecting piece 210 can now be inserted into cannula601 and advanced to the target region. As shown, the distal end portionof stimulator 300 is sized to fit and easily slide through the innerlumen of cannula 610 such that active and return electrodes 502, 504 canbe located at the desired depth/position and orientation in or aroundthe carotid sheath.

As shown in FIG. 12, a delivery stylet 700 may be used to providerigidity to the flexible tubing 201 and shaft of stimulator 300 toassist with the insertion process. A suitable delivery stylet may bepurchased commercially from AD-Tech Medical Instrument Corp. (1901William Street. Racine, Wis. 53401). Of course, it will be recognized bythose skilled in the art that stimulator 300 may be advanced to thetarget region in a variety of manners other than stylet 700. Once inplace, the system will be tested to ensure proper functioning, byactivating the source of electrical energy and noting the patient'sphysiological response, as described below.

As also shown in FIG. 12, cannula 601 may now be removed from thepatient. In one embodiment, this is accomplished by bending tabs 704,706 of base 612 downward and pulling them apart, thereby splittingcannula 601 into two pieces. Cannula 601 is then removed while thetubing 201 of stimulator 300 is held securely to prevent migrationduring cannula 601 removal. Similarly, delivery stylet 700 may beremoved from patient leaving only the stimulator 300 in position at thetarget region. Stimulator 300 is then secured in place within thepatient, as described above, for example using surgical glue and/or thedeployable springs shown in FIG. 7 or 8. Finally, the tubing 201 of thestimulator 300 is detached from the electrodes and withdrawn, and thepoint of entry on the patient's skin is bandaged. Alternatively, in anon-preferred embodiment, the tubing 201 is cut to a length ending nearskin level, plugged, and sutured just beneath the patient's skin,without being detached from the stimulator.

Monitoring methods may be used during the stimulation implantationprocedure to test whether the vagus nerve has been damaged during theprocedure. They would also be used after implantation to test operationof the stimulator and to confirm that the implanted stimulator can infact stimulate the vagus nerve as intended. Such methods have beendescribed for use during thyroid and brainstem surgery to monitor theintegrity of a vagus nerve, in which electromyographic monitoring of alaryngeal muscle is used as a safety indicator, and in which the vagusnerve is stimulated, for example, by an electrode placed in anendotracheal tube [SEVERTSON M A, Leonetti J P, Jarocki D. Vagal nervemonitoring: a comparison of techniques in a canine model. Am J Otol18(3, 1997):398-400; FRIEDRICH C, Ulmer C, Rieber F, Kern E, Kohler A,Schymik K, Thon K P, Lamadé W. Safety analysis of vagal nervestimulation for continuous nerve monitoring during thyroid surgery.Laryngoscope 122(9, 2012):1979-1987; DIONIGI G, Chiang F Y, Rausei S, WuC W, Boni L, Lee K W, Rovera F, Cantone G, Bacuzzi A. Surgical anatomyand neurophysiology of the vagus nerve (VN) for standardisedintraoperative neuromonitoring (IONM) of the inferior laryngeal nerve(ILN) during thyroidectomy. Langenbecks Arch Surg 395(7, 2010):893-899;SCHNEIDER R, Przybyl J, Pliquett U, Hermann M, Wehner M, Pietsch U C,König F, Hauss J, Jonas S, Leinung S. A new vagal anchor electrode forreal-time monitoring of the recurrent laryngeal nerve. Am J Surg 199(4,2010):507-514; PHELAN E, Potenza A, Slough C, Zurakowski D, Kamani D,Randolph G. Recurrent laryngeal nerve monitoring during thyroid surgery:normative vagal and recurrent laryngeal nerve electrophysiological data.Otolaryngol Head Neck Surg 147(4, 2012):640-646; SINGH R, Husain A M.Neurophysiologic intraoperative monitoring of the glossopharyngeal andvagus nerves. J Clin Neurophysiol. 2011 December; 28(6, 2011):582-586].

Methods have also been described for monitoring the vagus nerve duringopen surgery implantation of a vagus nerve stimulator [VAUGHN BV,Bernard E, Lannon S, Mann B, D'Cruz O F, Shockley W, Passanante A.Intraoperative methods for confirmation of correct placement of thevagus nerve stimulator. Epileptic Disord 3(2, 2001):75-78]. In acommonly assigned, co-pending application, entitled Devices and methodsfor monitoring non-invasive vagus nerve stimulation, which is herebyincorporated by reference, Applicant disclosed improved methods forverifying the operation of a vagus nerve stimulation device. Thosedisclosed methods may also be used during the implantation procedure toverify that the vagus nerve remains undamaged. As an example, thepatient may be requested to vocalize a vowel such as /a/ over severalvoice ranges (continuous glissando), before, during, and after theimplantation procedure. An acoustic analysis of the sounds may be usedto infer whether the vagus nerve is damaged and whether electricalstimulation of the vagus nerve by electrodes of the implanted stimulatoris in fact having an effect. This is because such electrical stimulationmay bring about subtle voice changes through its sensitive effect on abranch of the vagus nerve, the recurrent laryngeal nerve.

Although this disclosure relates specifically to the electricalstimulation of a vagus nerve, it will be appreciated that the systemsand methods of the present invention can be adapted for use with othertissues and nerves of the body, including but not limited to otherparasympathetic nerves, sympathetic nerves, spinal or cranial nerves,e.g., optic nerve, facial nerves, vestibulocochlear nerves and the like.In addition, embodiments of the present invention can be applied totreat symptoms of ailments or the ailments themselves, when used inconjunction with other procedures, including open procedures,intravascular procedures, interventional cardiology procedures, urology,laparoscopy, general surgery, arthroscopy, thoracoscopy or other cardiacprocedures, cosmetic surgery, orthopedics, gynecology,otorhinolaryngology, spinal and neurologic procedures, oncologyprocedures and the like.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A method for treating at least one of acondition or a symptom of a patient comprising: positioning astimulation device at a target site adjacent to a nerve within a patientor within a distance from the nerve such that one or more electricalimpulses generated with the stimulation device can reach and modulatethe nerve within the patient, the stimulation device comprising anantenna and one or more electrodes; transmitting electrical energy tothe antenna; generating one or more electrical impulses within thestimulation device with the electrical energy; applying the one or moreelectrical impulses to the nerve via the electrode, wherein the one ormore electrical impulses are sufficient to modulate the nerve and treatthe condition or symptom of the patient; and wherein the one or moreelectrical impulses have on periods wherein each of the electricalimpulses is generated and applied to the nerve and off periods betweenthe electrical impulses, wherein the electrical energy is transmitted tothe antenna during the off periods.
 2. The method of claim 1, whereinthe on periods have a duration of about 200 μS.
 3. The method of claim1, wherein the off periods have a duration of about 39,000 μS.
 4. Themethod of claim 1, wherein the transmitting step is carried out viaelectrical radiative coupling.
 5. The method of claim 1, wherein theelectrical energy is transmitted from a controller located externally tothe patient.
 6. The method of claim 1, wherein the one or moreelectrical impulses each have a fixed amplitude.
 7. The method of claim6, further comprising varying a duration of the one or more electricalimpulses via the stimulation device.
 8. The method of claim 1, whereineach of the one or more electrical impulses comprises one or morepulses, wherein each of the one or more pulses comprises a fixedamplitude and a fixed duration, and wherein each of the one or moreelectrical impulses comprises a duration equal to a combined duration ofthe fixed duration of each of the one or more pulses.
 9. The method ofclaim 8, further comprising varying the duration of each of the one ormore electrical impulses by varying a number of the one or more pulseswithin such electrical impulse.
 10. The method of claim 1, comprising:storing the electrical energy within the stimulation device; andreleasing the electrical energy from a storage device to a pulsegenerator within the stimulation device to generate the one or moreelectrical impulses.
 11. The method of claim 1, wherein the one or moreelectrical impulses have a fixed current.
 12. The method of claim 1,wherein the one or more electrical impulses have a fixed voltage. 13.The method of claim 1, wherein the electrical energy is transmitted viaa carrier signal comprising a frequency from about 800 MHz to about 1.2GHz.
 14. The method of claim 1, wherein the nerve is a vagus nerve. 15.A stimulation device for treating at least one of a condition or symptomof a patient comprising: an enclosure configured for positioningadjacent to a nerve within a neck of a patient or within a distance fromthe nerve such that one or more electrical impulses generated with thestimulation device can reach and modulate the nerve within the neck ofthe patient; an antenna coupled to the enclosure and configured toreceive an input signal from a power source located remotely from theenclosure, wherein the input signal comprises electrical energy; astorage device coupled to the antenna and housed within the enclosure,the storage device configured to store the electrical energy; a pulsegenerator coupled to the storage device within the enclosure andconfigured to generate one or more electrical impulses based on theelectrical energy, wherein the one or more electrical impulses have onperiods wherein each of the one or more electrical impulses is generatedand applied to the nerve and off periods between the on periods, whereinthe pulse generator is configured to generate and apply the one or moreelectrical impulses such that the electrical energy is received by theantenna and stored within the storage device during the off periods ofthe one or more electrical impulses; and one or more electrodes housedwithin the enclosure and coupled to the pulse generator, wherein the oneor more electrodes are configured to conduct the one or more electricalimpulses to the nerve sufficient to modulate the nerve.
 16. Thestimulation device of claim 15, wherein each of the one or moreelectrical impulses comprise one or more pulses having a fixed amplitudeand a fixed duration, wherein the one or more electrical impulses eachcomprise a duration equal to a combined duration of the fixed durationof each of the one or more pulses.
 17. The stimulation device of claim15, wherein the on periods have a duration of about 200 μS.
 18. Thestimulation device of claim 15, wherein the off periods have a durationof about 39,000 μS.
 19. The stimulation device of claim 16, wherein thepulse generator is configured to vary a number of the one or more pulseswithin the one or more electrical impulses to vary the duration of theone or more electrical impulses.
 20. The stimulation device of claim 15,wherein the antenna is housed within the enclosure.
 21. The stimulationdevice of claim 16, wherein the fixed duration of each of the one ormore pulses is from about 100 μS to about 1000 μS.
 22. The stimulationdevice of claim 15, wherein the input signal is received from the powersource through electrical radiative coupling on a carrier signalcomprising a frequency from about 300 MHz to about 6 GHz.
 23. Thestimulation device of claim 15, wherein the one or more electricalimpulses comprise a frequency from about 1 Hz to about 50 Hz.